The switch from trivalent to bivalent oral poliovirus vaccine: Will it lead to polio?

bivalent OPVIn four months, 155 countries will together switch from using trivalent to bivalent oral poliovirus vaccine. Will this change lead to more cases of poliomyelitis?

There are three serotypes of poliovirus, each of which can cause paralytic poliomyelitis. The Sabin oral poliovirus vaccine (OPV), which has been used globally by WHO in the eradication effort, is a trivalent vaccine that contains all three serotypes.

In September 2015 WHO declared that wild poliovirus type 2 has been eradicated from the planet – no cases caused by this serotype had been detected since November 1999. However, in 2015, there were 9 cases of poliomyelitis caused by the type 2 vaccine. For these reasons WHO decided to remove the type 2 Sabin strain from OPV, and switch from trivalent to bivalent vaccine in April 2016.

After OPV is ingested, the viruses replicate in the intestinal tract, providing immunity to subsequent infection. During replication in the intestine, the vaccine viruses lose the mutations that prevent them from causing paralysis. Everyone who receives OPV sheds these revertant viruses in the feces. In rare cases (about one in 1.5 million) the revertant viruses cause poliomyelitis in the vaccine recipient (these cases are called VAPP for vaccine-associated paralytic poliomyelitis). Vaccine-derived polioviruses can also circulate in the human population, and in under-vaccinated populations, they can cause poliomyelitis.

There were 26 reported cases of poliomyelitis caused by the type 1 or type 2 vaccine viruses in 2015. Nine cases of type 2 vaccine-associated polio were detected in four countries: Pakistan, Guinea, Lao People’s Democratic Republic, and Myanmar. Removing the type 2 strain from OPV will eliminate vaccine-associated poliomyelitis in recipients caused by this serotype. When the US switched from OPV to the inactivated poliovaccine (IPV) in 2000, VAPP was eliminated.

The problem with the trivalent to bivalent switch is that vaccine-derived type 2 poliovirus is likely still circulating somewhere on Earth. The last two reported cases of type 2 vaccine-associated polio in 2015 were reported in Myanmar in October. The viruses isolated from these cases were genetically related to strains that had been circulating in the same village in April of the that year. In other words, type 2 vaccine-derived strains have been circulating for an extended period of time in Myanmar; they have been known to persist for years elsewhere. If these viruses continue to circulate past the time that immunization against type 2 virus stops, they could pose a threat to the growing numbers of infants and children who have not been immunized against this serotype.

Eventually as type 3, and then type 1 polioviruses are eradicated, it will also be necessary to stop immunizing with the respective Sabin vaccine strains. The switch from trivalent to bivalent vaccine in April 2016 is essentially an experiment to determine if it is possible to stop immunizing with OPV without placing newborns at risk from circulating vaccine-derived strains.

Over 18 years ago Alan Dove and I argued that the presence of circulating vaccine-derived polioviruses made stopping immunization with OPV a bad idea. We suggested instead a switch from OPV to IPV until circulating vaccine-derived viruses disappeared. At the time, WHO disagreeed, but now they recommend that all countries deliver at least one dose of IPV as part of their immunization program. Instead of simply removing the Sabin type 2 strain from the immunization programs of 155 countries, it should be replaced with the inactivated type 2 vaccine. This change would maintain immunity to this virus in children born after April 2016. Such a synchronized replacement is currently not in the WHO’s polio eradication plans. I hope that their strategy is the right one.

TWiV 371: Sympathy for the devil

TWiVOn episode #371 of the science show This Week in Virology, the TWiVologists discuss the finding of a second transmissible cancer in Tasmanian devils, and development of new poliovirus strains for the production of inactivated vaccine in the post-eradication era.

You can find TWiV #371 at www.microbe.tv/twiv.

Virologists, start your poliovirus destruction!

I have worked on poliovirus for over thirty-six years, first as a posdoctoral fellow with David Baltimore in 1979, and then in my laboratory at Columbia University. The end of that research commences this year with the destruction of my stocks of polioviruses.

In 2015 there were 70 reported cases of poliomyelitis caused by wild type 1 poliovirus, and 26 cases of poliomyelitis caused by circulating vaccine derived polioviruses (cVDPV) types 1 and 2. The last case of type 2 poliovirus occurred in India in 1999, and the virus was declared eradicated in 2015. Consequently the World Health Organization has decided that all remaining stocks of wild type 2 poliovirus should be destroyed by the end of 2015.

My laboratory has worked extensively with type 2 polioviruses. Before we produced transgenic mice susceptible to poliovirus, we had studied the Lansing strain of type 2 poliovirus because it had the unusual ability to infect wild type mice (polioviruses normally only infect certain primates). We determined the nucleotide sequence of the viral genome, identified the capsid as a determinant of the ability of the virus to infect wild type mice, and showed that swapping an eight amino acid sequence of capsid protein VP1 from a type 1 strain with that from Lansing conferred the ability to infect non-transgenic mice. These findings indicate that the ability of the Lansing strain of poliovirus to infect mice is likely due to recognition by the viral capsid of a receptor in the mouse central nervous system. In the past year we took advantage of the ability to produce mouse neurons from stem cells to attempt to identify the murine cellular receptor for Lansing virus.

To prevent further cases of poliomyelitis caused by cVDPVs, WHO has decided that there will be a synchronized, global switch from trivalent OPV to bivalent OPV in April 2016. By July of 2016 all remaining stocks of the Sabin type 2 poliovirus strains, which are used to produce OPV, will also be destroyed.

No wild type 3 poliovirus has been detected since November 2012, and it is likely that this virus will be declared eradicated within the next several years. At that time we will have to destroy our stocks of type 3 poliovirus. That leaves wild poliovirus type 1, which circulates only in Pakistan and Afghanistan. Given the small number of cases of paralysis caused by this type, it is reasonable to believe that eradication will occur within the next five years. If this timeline is correct, it means that I will be destroying my last vials of poliovirus around 2020.

It is of course necessary to destroy stocks of wild and vaccine polioviruses to prevent reintroduction of the virus and the disease that it causes. The 1978 release of smallpox virus from a laboratory in the United Kingdom, which caused one death, lead to requests for reducing the number of laboratories that retained the virus. Today there are just two official repositories of smallpox virus in the United States and Russia.

It is rare for an investigator to be told to destroy stocks of the virus that is the subject of his or her research. Over the years we have published 81 papers on poliovirus replication, vaccines, and pathogenesis. While I realize that it is absolutely essential to stop working on this virus, I do so with a certain amount of sadness. What other emotion could I have for a virus on which I have expended so much thought and effort?

Image: Poliovirus by Jason Roberts

Correction: The synchronized switch in April 2016 is from trivalent to bivalent OPV, not OPV to IPV. Consequently I have removed comments related to an OPV-IPV switch.

Why do we still use Sabin poliovirus vaccine?

VAPPThe Sabin infectious, attenuated poliovirus vaccines are known to cause vaccine-associated paralysis in a small number of recipients. In contrast, the Salk inactivated vaccine does not cause poliomyelitis. Why are the Sabin vaccines still used globally? The answer to this question requires a brief visit to the history of poliovirus vaccines.

The inactivated poliovirus vaccine (IPV) developed by Jonas Salk was licensed for use in 1955. This vaccine consists of the three serotypes of poliovirus whose infectivity, but not immunogenicity, is destroyed by treatment with formalin. When prepared properly, IPV does not cause poliomyelitis (early batches of IPV were not sufficiently inactivated, leading to vaccine-associated outbreaks of polio, the so-called Cutter incident). From 1955 to 1960 cases of paralytic poliomyelitis in the United States dropped from 20,000 per year to 2,500.

While Salk’s vaccine was under development, several investigators pursued the production of infectious, attenuated vaccines as an alternative. This approach was shown to be effective by Max Theiler, who in 1937 had made an attenuated vaccine against yellow fever virus by passage of the virulent virus in laboratory mice. After many passages, the virus no longer caused disease in humans, but replicated sufficiently to induce protective immunity. Albert Sabin capitalized on these observations and developed attenuated versions of the three serotypes of poliovirus by passage of virulent viruses in different animals and cells. In contrast to Theiler’s yellow fever vaccine, which was injected, Sabin’s poliovirus vaccines were designed to be taken orally – hence the name oral poliovirus vaccine (OPV). As in a natural poliovirus infection, Sabin’s vaccines would replicate in the intestinal tract and induce protective immunity there and in the bloodstream.

Sabin began testing his attenuated vaccines in humans in 1954. By 1957 there was evidence that the virus that was fed to volunteers was not the same as the virus excreted in the feces. As Sabin writes:

It was evident, however, that as in the young adult volunteers, the virus in some of the stool specimens had a greater neurovirulence than the virus originally swallowed in tests in monkeys.

What Sabin did not know was whether the change in neurovirulence of his vaccine strains constituted a threat to the vaccine recipients and their contacts, a question that could only be answered by carrying out larger clinical trials. Many felt that such studies were not warranted, especially considering the success of IPV in reducing the number of paralytic cases. Sabin notes that his friend Tom Rivers, often called the father of American virology, told him to ‘discard the large lots of OPV that I had prepared into a suitable sewer’.

Despite the opposition to further testing of OPV in the US, others had different views. An international committee of the World Health Organization recommended in 1957 that larger trials of OPV should be carried out in different countries. Sabin’s type 2 vaccine was given to 200,000 children during an outbreak of polio in Singapore in 1958, and follow-up studies revealed no safety problems. In Czechoslovakia 140,000 children were given OPV and subsequent studies revealed that the virus spread to unimminized contacts but did not cause disease.

Perhaps the most important numbers came from trials of OPV in the Soviet Union. Sabin had been born in Russia and had close contacts with Soviet virologists, including Mikhail Chumakov, director of the Poliomyelitis Research Institute in Moscow. Chumakov was not satisfied with the results of IPV trials in his country and asked Sabin to send him OPV for testing. By the end of 1959 nearly 15,000,000 people had been given OPV in different parts of the Soviet Union with no apparent side effects. Dorothy Horstmann, a well known virologist at Yale University, was sent to the Soviet Union to evaluate the outcome of the trials. Horstmann writes:

It was clear that the trials had been carefully carried out, and the results were monitored meticulously in the laboratory and in the field. By mid-1960 approximately 100 million persons in the Soviet Union, Czechoslovakia, and East Germany had received the Sabin strains. Of great importance was the demonstration that the vaccine was safe, not only for the recipients, but for the large numbers of unvaccinated susceptible who must have been exposed as contacts of vaccines.

The results obtained from these trials in the Soviet Union convinced officials in the US and other countries to carry out clinical trials of OPV. In Japan, Israel, Chile, and other countries, OPV was shown to be highly effective in terminating epidemics of poliomyelitis. In light of these findings, all three of Sabin’s OPV strains were approved for use in the US, and in 1961-62 they replaced IPV for routine immunization against poliomyelitis.

As soon as OPV was used in mass immunizations in the US, cases of vaccine-associated paralysis were described. Initially Sabin decried these findings, arguing that temporal association of paralysis with vaccine administration was not sufficient to implicate OPV. He suggested that the observed paralysis was caused by wild-type viruses, not his vaccine strains.

A breakthrough in our understanding of vaccine-associated paralysis came in the early 1980s when the recently developed DNA sequencing methods were used to determine the nucleotide sequences of the genomes of the Sabin type 3 vaccine, the neurovirulent virus from which it was derived, and a virus isolated from a child who had developed paralysis after administration of OPV. The results enumerated for the first time the mutations that distinguish the Sabin vaccine from its neurovirulent parent. More importantly, the genome sequence of the vaccine-associated isolate proved that it was derived from the Sabin vaccine and was not a wild-type poliovirus.

We now understand that every recipient of OPV excretes, within a few days, viruses that are more neurovirulent that the vaccine strains. This evolution occurs because during replication of the OPV strains in the human intestine, the viral genome undergoes mutation and recombination that eliminate the attenuating mutations that Sabin so carefully selected by passage in different hosts.

From 1961 to 1989 there were an average of 9 cases (range, 1-25 cases) of vaccine-associated paralytic poliomyelitis (VAPP) in the United States, in vaccine recipients or their contacts, or 1 VAPP case per 2.9 million doses of OPV distributed (illustrated). Given this serious side effect, the use of OPV was evaluated several times by the Institute of Medicine, the Centers for Disease Control and Prevention, and the Advisory Committee on Immunization Practices. Each time it was decided that the risks associated with the use of OPV justified the cases of VAPP. It was believed that a switch to IPV would lead to outbreaks of poliomyelitis, because: OPV was better than IPV at protecting non-immunized recipients; the need to inject IPV would lead to reduced compliance; and IPV was known to induce less protective mucosal immunity than OPV.

After the WHO began its poliovirus eradication initiative in 1988, the risk of poliovirus importation into the US slowly decreased until it became very difficult to justify routine use of OPV. In 1996 the Advisory Committee on Immunization Practices decided that the US would transition to IPV and by 2000 IPV had replaced OPV for the routine prevention of poliomyelitis. As a consequence VAPP has been eliminated from the US.

OPV continues to be used in mass immunization campaigns for the WHO poliovirus eradication program, because it is effective at eliminating wild polioviruses, and is easy to administer. A consequence is that neurovirulent vaccine-derived polioviruses (VDPV) are excreted by immunized children. These VDPVs have caused outbreaks of poliomyelitis in areas where immunization coverage has dropped. Because VDPVs constitute a threat to the eradication campaign, WHO has recommended a global transition to IPV. Once OPV use is eliminated, careful environmental surveillance must be continued to ensure that VDPVs are no longer present before immunization ceases, a goal after eradication of poliomyelitis.

As a virologist working on poliovirus neurovirulence, I have followed the vaccine story since I joined the field in 1979. I have never understood why no cases of VAPP were observed in the huge OPV trials carried out in the Soviet Union. Had VAPP been identified in these trials, OPV might not have been licensed in the US. Global use of OPV has led to near global elimination of paralytic poliomyelitis. Would the exclusive use of IPV have brought us to the same point, without the unfortunate cases of vaccine-associated paralysis? I’m not sure we will ever know the answer.

Update: As recently as 1997 DA Henderson, architect of smallpox eradication, argued that developed countries should not use IPV, because it ‘implies accepting the potential of substantial penalties while reducing but not eliminating, an already extremely small risk of vaccine-associated paralytic illness’.

An unexpected benefit of inactivated poliovirus vaccine

Poliovirus by Jason Roberts

Poliovirus by Jason Roberts

The polio eradication and endgame strategic plan announced by the World Health Organization in 2014 includes at least one dose of inactivated poliovirus vaccine (IPV). Since 1988, when WHO announced the polio eradication plan, it had relied exclusively on the use of oral poliovirus vaccine (OPV). The rationale for including a dose of IPV was to avoid outbreaks of vaccine-derived type 2 poliovirus. This serotype had been eradicated in 1999 and had consequently been removed from OPV. However IPV, which is injected intramuscularly and induces highly protective humoral immunity, is less effective in producing intestinal immunity than OPV. This property was underscored by the finding that wild poliovirus circulated in Israel during 2013, a country which had high coverage with IPV. Furthermore, in countries that use only IPV, over 90% of immunized children shed poliovirus after oral challenge. I have always viewed this shortcoming of IPV as problematic, in view of the recommendation of the World Health Organization to gradually shift from OPV to IPV. Even if the shift to IPV occurs after eradication of wild type polioviruses, vaccine-derived polioviruses will continue to circulate because they cannot be eradicated by IPV. My concerns are now mitigated by new results from a study in India which indicate that IPV can boost intestinal immunity in individuals who have already received OPV.

To assess the ability of IPV to boost mucosal immunity, 954 children in three age groups (6-11 months, 5 and 10 years) were immunized with IPV, bivalent OPV (bOPV, containing types 1 and 3 only), or no vaccine. Four weeks later all children were challenged with bOPV, and virus shedding in the feces was determined 0, 3, 7, and 14 days later. The results show that 8.8, 9.1, and 13.5% of children in the 6-11 month, 5-year and 10-year old groups shed type 1 poliovirus in feces, compared with 14.4, 24.1, and 52.4% in the control group. Immunization with IPV reduced fecal shedding of poliovirus types 1 (39-74%) and 3 (53-76%). The reduction of shedding was greater after immunization with IPV compared with bOPV.

This study shows that a dose of IPV is more effective than OPV at boosting intestinal immunity in children who have previously been immunized with OPV. Both IPV and OPV should be used together in the polio eradication program. WHO therefore recommends the following vaccine regimens:

  • In all countries using OPV only, at least 1 dose of type 2 IPV should be added to the schedule.
  • In polio-endemic countries and in countries with a high risk for wild poliovirus importation and spread: one OPV birth dose, followed by 3 OPV and at least 1 IPV doses.
  • In countries with high immunization coverage (90-95%) and low wild poliovirus importation risk: an IPV-OPV sequential schedule when VAPP is a concern, comprising 1-2 doses of IPV followed by 2 or mores doses of OPV.
  • In countries with both sustained high immunization coverage and low risk of wild poliovirus importation and transmission: an IPV only schedule.

Type 2 OPV will be gradually removed from the global immunization schedules. There have been no reported cases of type 3 poliovirus since November 2012. If this wild type virus is declared eradicated later this year, presumably WHO will recommend withdrawal of type 3 OPV and replacement with type 3 IPV.

All 342 confirmed cases of poliomyelitis in 2014 were caused by type 1 poliovirus in 9 countries, mainly Pakistan and Afghanistan. Given the social and political barriers to immunization, it will likely take many years to eradicate this serotype.

Oral polio vaccine-associated paralysis in a child despite previous immunization with inactivated virus

Poliovirus by Jason Roberts

Poliovirus by Jason Roberts

Vaccine-associated poliomyelitis caused by the oral poliovirus vaccine is rare, but its occurrence in a healthy, immunocompetent 6-month old child was highly unusual because the child had been previously immunized with two doses of the injected, inactivated poliovirus vaccine (IPV).

The three poliovirus vaccine strains developed by Albert Sabin (OPV, oral poliovirus vaccine) contain mutations which prevent them from causing paralytic disease. When the vaccine is ingested, the viruses replicate in the intestine, and immunity to infection develops. While replicating in the intestinal tract, the vaccine viruses undergo mutation, and OPV recipients excrete neurovirulent polioviruses. These so-called vaccine-derived polioviruses (VDPV) can cause poliomyelitis in the recipient of the vaccine or in a contact. During the years that the Sabin poliovirus vaccines were used in the US, cases of poliomyelitis caused by VDPV occurred at a rate of about 1 per 1.4 million vaccine doses, or 7-8 per year. Once the disease was eradicated from the US in 1979, the only cases of polio were caused by the Sabin vaccine.

To prevent vaccine-associated poliomyelitis, in 1997 the US switched to an immunization schedule consisting of two doses of IPV followed by one dose of OPV. The US then switched to using IPV exclusively in 2000. The child in this case essentially had a polio immunization course similar to that utilized in the US from 1997-2000: two doses of IPV, one dose of OPV. Why did the child develop poliomyelitis?

One clue comes from the fact that after the switch to an IPV-OPV schedule in 1997, there were still three cases of VAPP in 1998 and three in 1999. Another hint comes from a study of immune responses in children given multiple doses of IPV. Most of the children receiving two doses of IPV produced antibodies against types 1 and 2 poliovirus (92 and 94%), but only 74% of children produced antibodies against type 3 poliovirus.

The final piece of information needed to solve this puzzle is that the child in this case had vaccine-associated poliovirus caused by the type 3 strain, which was isolated from his feces.

Therefore, the child in this case most likely did not produce sufficient antibodies to type 3 poliovirus after receiving the two doses of IPV. As a consequence, when he was given OPV, he developed type 3 vaccine-associated poliomyelitis.

This case of VAPP could have been prevented: the child was born in Canada, and as customary in that country since 1995, he received two doses of IPV. At 5 months of age the child and his family visited China, where his parents decided to continue his immunizations according to the local schedule. China still uses OPV, so that is what the child received.

Implications of finding poliovirus in sewers of Brazil and Israel

Poliovirus by Jason RobertsWild poliovirus has been detected in the sewers of Brazil and Israel. Fortunately, no cases of poliomyelitis have been reported in either country. Why is poliovirus present in these countries and what are the implications for the eradication effort?

Wild type poliovirus (e.g. not vaccine-derived virus) was detected in sewage samples that had been collected in March 2014 at Viracopos International Airport in the State of Sao Paulo. Wild type poliovirus had not been detected in Brazil since 1989 when the last case of poliomyelitis was reported in that country, and has not been found since March 2014.

Sequence analysis of the RNA genome of the wild type poliovirus found in the Brazilian sewer indicates that it is closely related to an isolate from a case of poliomyelitis in Equatorial Guinea. It seems likely that this virus was carried to Brazil in the intestine of an infected person who did not have symptoms of paralytic disease (only 1 in 100 poliovirus infections lead to paralysis). This individual might have traveled from Equatorial Guinea to the Brazilian airport where use of the bathroom lead to introduction of poliovirus into the sewer.

There have been 8 reported cases of poliomyelitis in Equatorial Guinea in 2014, from which we can extrapolate that there have been approximately 800 infected individuals. Given the number of cases of poliomyelitis that have been reported globally over the past 20 years, it is surprising that virus has not been detected previously in Brazilian sewage, especially at the airport. I suspect that wild type poliovirus would be detected in sewage in the US, given the number of individuals who enter that country each day. However the US does not conduct routine surveillance for poliovirus in sewage.

Brazil utilizes the Sabin vaccine to control poliomyelitis, and in the past 8 years over 95% immunization coverage has been achieved. The Sabin vaccine is taken orally and replicates in the intestine where it induces mucosal immunity. The intestine of Brazilians do not support the replication of wild type poliovirus, which is why the presence of wild type virus in sewage is not a threat – it is unlikely to spread in the population.

The isolation* of wild type poliovirus from sewage and from stool samples in Israel is a far more serious matter. As with Brazil, there have been no reported cases of poliomyelitis in Israel since 1989. Yet ten different sites in central and south Israel have been persistently positive for wild type poliovirus since February 2013. Wild type poliovirus has been found intermittently at 8 of 47 different sampled sites in southern and central Israel, and in stool from healthy persons collected in July 2013.

Two major lineages of wild type polioviruses currently circulate in endemic countries: the South Asian (SOAS) lineage in Pakistan and Afghanistan, andthe West African lineage in Nigeria. Nucleotide sequence analysis of the wild type poliovirus isolates from Israel indicate that they are closely related to the South Asian lineage, and in particular to polioviruses that circulated in Pakistan in 2012 and in Egypt in 2012. Molecular clock analysis of the sequences indicate that poliovirus was probably transmitted in 2012 from Pakistan into Egypt and Israel, and then spread in the latter country.

The central point of poliovirus circulation is within Bedouin communities in the south of Israel. The main virus reservoir within this community is children less than 9 years of age who had been immunized with inactivated poliovirus vaccine (IPV). This vaccine has been exclusively used in Israel since 2005, with overall vaccination coverage between 92-95%, and 81-100% within individual districts. The last nine birth cohorts in this country have been immunized solely with IPV.

The response to isolation of wild type poliovirus in Israeli sewers was to complete IPV immunization of all children in the south, raising coverage to above 99%. Then from August 2013 onwards, all children up to the age of nine years old were given a dose of bivalent oral poliovirus vaccine (OPV) containing types 1 and 3 poliovirus. All children who received OPV had previously been immunized with IPV, a strategy that prevents vaccine-associated poliomyelitis.

The finding of sustained circulation of wild type poliovirus in Israel shows that the virus can circulate silently in a population that has been well immunized with IPV. Such circulation occurs because IPV does not sufficiently protect the intestinal tract against poliovirus infection. However poliomyelitis does not occur in such populations because IPV-induced antibodies in the blood prevent virus invasion into the central nervous system. The US now exclusively uses IPV and it is likely that wild polioviruses are present in US sewage, although as mentioned above the US does not search for poliovirus in sewage. Silent circulation of wild type poliovirus in countries that use IPV poses a threat to other countries where immunization coverage is low.

These findings indicate that immunization with IPV will not lead to eradication of wild type poliovirus. This observation is problematic because the World Health Organization has recommended a gradual shift from OPV to IPV. In the past I have also supported such a transition, but I have also remained cautious about the ability of IPV to immunize the human gut. The experience in Israel confirms my suspicions.

The US shifted from using OPV to IPV because the associated vaccine-associated poliomyelitis was not acceptable in a country with no paralytic disease caused by wild type poliovirus. Now it seems that eradication cannot be achieved with IPV. What can be done about this conundrum? OPV should be used to eradicate remaining pools of wild type poliovirus in endemic countries (Nigeria, Afghanistan, Pakistan). At the same time environmental surveillance must be done in all countries that exclusively use IPV. If wild type poliovirus is found in the sewage of such countries, then introduction of OPV, in children previously immunized with IPV, should be considered to eliminate the reservoir of will type virus. It will be important to observe the effect of the distribution of OPV in Israel on the circulation of wild type poliovirus.

*Infectious poliovirus was isolated by adding sewer and stool filtrates to monolayers of L20B cells, which are mouse fibroblasts that produce the cellular receptor for poliovirus. These cells were produced in my laboratory, and are useful for isolating polioviruses because they are not susceptible to infection with non-polio enteroviruses. I am pleased to be able to contribute to efforts to control poliomyelitis.

World Polio Day

gold poliovirus

Image credit: Jason Roberts

As a virologist who has worked on poliovirus since 1979, I would be remiss if I did not note that today, 24 October, is World Polio Day. World Polio Day was established by Rotary International over a decade ago to commemorate the birth of Jonas Salk, who led the first team to develop a vaccine against poliomyelitis.

The polio eradication effort has made impressive progress towards eliminating polio from the planet. In 1988 it was estimated that there were a total of 350,000 cases of poliomyelitis (probably an underestimate); as of this writing there have been 301 cases in 2013, which is unfortunately already more than in all of 2012 (223). Some setbacks to the program include an outbreak in the Horn of Africa, the finding of wild poliovirus (but no paralytic cases) in Israel, and two suspected cases in Syria. Transmission of wild poliovirus has never been interrupted in three countries: Afghanistan, Nigeria, and Pakistan. The good news is that India remains polio-free, a remarkable achievement.

Currently the eradication effort mainly utilizes the Sabin oral poliovirus vaccine strains (OPV). These vaccines are taken orally and replicate in the intestine, followed by entry into the bloodstream. They induce antiviral immunity in both the intestine and the blood. However, a drawback to using the Sabin vaccines is that the viruses revert to neurovirulence during replication in the intestine. As a consequence, virulent polioviruses are shed in the feces. These can cause poliomyelitis, either in the vaccine recipient or in unimmunized contacts. As wild polioviruses are eliminated, vaccine-derived polioviruses will continue to circulate, necessitating ‘vaccinating against the vaccine’. As a consequence, WHO has proposed a switch to the inactivated poliovirus vaccine, IPV, which if prepared properly cannot cause poliomyelitis.

A very good question is whether the use of IPV can lead to elimination of poliovirus from the planet. Consider the following scenario: at some point in the future the use of Sabin vaccines is discontinued, and all polio immunizations are done with IPV. Vaccine-derived polioviruses will still be present, and possibly also wild polioviruses. As shown by the recent detection of poliovirus in Israel, poliovirus can replicate in the intestines of individuals who have been immunized with IPV. Therefore, in a post-OPV world, immunization with IPV will still allow circulation of vaccine-derived polioviruses. As long as immunization continues at a high rate, there should be no cases of paralytic disease – but we already know that high immunization coverage is difficult to maintain. How long will we need to immunize with IPV before circulation of vaccine-derived polioviruses will stop?

Below are links to resources on polio, provided by David Gold at Global Health Strategies:

  • An expert panel including Dr. Bruce Aylward, WHO’s Assistant Director-General for Polio, will discuss the status of eradication today at Rotary International’s ‘Making History‘ event. Help share and watch live at 6:30 PM ET.
  • Look out for A Shot to Save the World, a documentary about Jonas Salk’s vaccine discovery, airing on the Smithsonian Channel today at 8:00 pm ET/PT.
  • President-elect of the Asia Pacific Pediatric Association Naveen Thacker wrote an opinion piece on India’s incredible achievements against polio, and the benefits and lessons India’s experience offers. Help share his piece.
  • Check out a video by footballer Leo Messi (tweet), a blog post by Paralympian polio-survivor Dennis Ogbe (tweet), a Vaccines Today blog post by Ramesh Ferris (tweet) and an Impatient Optimists post on other ways to get involved today.
  • Pakistan: Thanks to the work of heroic vaccinators, Pakistan has eliminated polio from much of the country. This year, 74% of cases, and 93% during the high season, have occurred in one region: the Federally Administered Tribal Areas (FATA) of northern Pakistan. North Waziristan, in FATA, has been inaccessible since June 2012, and has reported 14 wild polio cases this year in an increasingly severe outbreak. The program is intensifying immunizations in neighboring areas to prevent spread, but continued inaccessibility in this region poses a serious risk to the global effort.
  • Nigeria: Challenges persist in northern Nigeria, particularly in Borno and Kano, but other traditional reservoir areas appear to be largely polio-free — reminders that success is possible. Of particular importance, the northwest of the country, from which polio has historically spread into West Africa, has not had any cases this year. Read and help share a recent Science article (available with free registration) that takes an in-depth look at Nigeria’s eradication efforts.
  • Afghanistan: Afghanistan’s traditionally endemic Southern Region remains polio-free, with all cases this year linked to cross-border transmission with Pakistan. Next month will mark one year since the last case was recorded in the Southern Region.
  • Horn of Africa: GPEI partners responded rapidly to the outbreak, and we’re seeing signs of progress: there have been no confirmed cases in the Banadir region of Somalia, the epicenter of the outbreak, or in Kenya, since August. The number of unimmunized individuals in the region still poses a major risk for further spread. Outbreak response will continue aggressively into 2014.
  • Possible Polio Cases Detected in Syria: Syria reported a cluster of possible polio cases on 17 October that is currently being investigated. The country has been polio-free since 1999, but is considered at high risk for polio due to declining immunization rates. Syria’s Ministry of Health is preparing an urgent response across the country, aiming to conduct the first campaign by the end of October. Supplementary immunization activities are being planned in neighboring countries, including Lebanon, Jordan, Egypt, southern Turkey and western Iraq. The GPEI has a history of eliminating polio in areas of insecurity. Drawing from past successful efforts in insecure areas, including El Salvador and Angola, the Strategic Plan outlines approaches to eliminating polio in areas of conflict that are informing Syria’s response.
  • IMB Report: The International Monitoring Board (IMB), tasked with assessing the GPEI effort each quarter, met earlier this month to review the program’s progress, challenges and risks in endemic countries, the Horn of Africa and Israel. The IMB’s report from this meeting will be available here on Friday, 25 October

 

WHO will switch to type 2 inactivated poliovirus vaccine

Poliovirus by Jason RobertsThe World Health Organization’s campaign to eradicate poliomyelitis made impressive inroads in 2012: only 212 cases were reported, compared with 620 the previous year; moreover, India remained polio-free. The dark side of this story is that as wild polio is eliminated, vaccine-associated poliomyelitis moves in to take its place. The landmark decision by WHO to replace the infectious, type 2 Sabin poliovaccine with inactivated vaccine is an important step towards eliminating vaccine-associated polio.

A known side effect of the Sabin poliovirus vaccines, which are taken orally and replicate in the intestine, is vaccine-associated poliomyelitis. During the years that the Sabin poliovirus vaccines (also called oral poliovirus vaccine, or OPV) were used in the US, cases of poliomyelitis caused by vaccine-derived polioviruses (VDPV) occurred at a rate of about 1 per 1.4 million vaccine doses, or 7-8 per year. Once the disease was eradicated from the US in 1979, the only cases of polio were caused by VDPVs. For this reason the US switched to the Salk inactivated poliovirus vaccine (IPV) in 2000.

The main vaccine used by WHO in the global eradication effort has been a trivalent preparation comprising all three serotypes. When type 2 poliovirus was eradicated in 1999, many countries began immunizing only against types 1 and 3 poliovirus. As a consequence of this immunization strategy, population immunity to type 2 poliovirus declined. This switch, together with poor routine immunization coverage in some areas, has lead to polio outbreaks caused by cVDPV2 in countries such as Pakistan.

Alan Dove and I suggested in 1997 that it would be necessary to switch from OPV to IPV to achieve polio eradication. However, WHO did not agree with our position:

Dove and Racaniello believe that the reliance of the WHO on the live Sabin oral poliovirus vaccine (OPV) means that there will be a continuing threat of release of potentially pathogenic virus into the environment. They therefore recommend a switch to the inactivated polio vaccine (IPV). In response, Hull and Aylward explain why a switch from OPV is not necessary and describe the studies being sponsored by the WHO to determine how and when immunization can safely be ended.

I remember well the words of DA Henderson, the architect of smallpox eradication, when I proposed a switch to IPV at a conference in 2001:

There is no way it is going to come about and as an end-game strategy it is dreaming to believe that this is reasonable. So, it is just not on.

Apparently I was not dreaming: in May 2012 the 65th World Health Assembly requested that the Director-General “coordinate with all relevant partners, including vaccine manufacturers, to promote the research, production and supply of vaccines, in particular inactivated polio vaccines, in order to enhance their affordability, effectiveness and accessibility”. Later last year the Strategic Advisory Group of Experts on immunization (SAGE) called for a global switch from trivalent to bivalent OPV, eliminating the type 2 component. To ensure that circulating type 2 VDPVs do not pose a threat, SAGE also recommended that all countries introduce at least one dose of inactivated poliovaccine. This decision was announced in the 4 January 2013 Weekly Epidemiological Record (pdf).

The fact that WHO believes it is necessary to switch from type 2 OPV to IPV surely means that in the future, when types 1 and 3 polioviruses are eradicated, types 1 and 3 OPV will be replaced with IPV. This is the correct endgame strategy for eradicating polio. Once circulating VDPVs are no longer detectable on the planet – something that will probably not happen before 2020 – then we may safely stop immunization with IPV.

Poliovirus image courtesy of Jason Roberts.

Vaccine-associated poliomyelitis in Pakistan

Poliovirus by Jason RobertsAn outbreak of ten cases of poliomyelitis caused by circulating vaccine-derivied poliovirus type 2 (cVDPV2) is ongoing in Pakistan, centered in the Kila Abdulla/Pishin area of Baluchistan. The same virus strain has spread to the neighboring Kandahar province in Afghanistan, where two paralytic cases have been reported. Vaccine-derived poliomyelitis is a well-known consequence of immunization with the Sabin poliovirus vaccine.

There are three serotypes of poliovirus, each of which causes poliomyelitis. The three vaccine strains developed by Albert Sabin (OPV, oral poliovirus vaccine) contain mutations which prevent them from causing paralytic disease. When the vaccine is taken orally, the viruses replicate in the intestine, and immunity to infection develops. While replicating in the intestinal tract, the vaccine viruses undergo genetic changes. As a consequence, the OPV recipients excrete neurovirulent polioviruses. These so-called vaccine-derived polioviruses (VDPV) can cause poliomyelitis in the recipient of the vaccine or in a contact. During the years that the Sabin poliovirus vaccines were used in the US, cases of poliomyelitis caused by VDPV occurred at a rate of about 1 per 1.4 million vaccine doses, or 7-8 per year. Once the disease was eradicated from the US in 1979, the only cases of polio were caused by VDPVs. For this reason the US switched to the Salk (inactivated) poliovirus vaccine in 2000.

Because VDPVs are excreted in the feces, they can spread in communities. These circulating VDPVs, or cVDPVs, can cause outbreaks of poliomyelitis in under-immunized populations. Examples include outbreaks of poliomyelitis in an Amish community and in Nigeria in 2009 caused by cVDPV2. Nigeria employed trivalent OPV before 2003, the year that this country began a boycott of polio immunization. Because type 2 poliovirus had been eradicated from the globe in 1999, when immunization in Nigeria resumed in 2004, monovalent types 1 and 3 vaccine were used. The source of the VDPV type 2 in Nigeria was the trivalent vaccine used before 2003.

For many years the vaccine used by WHO in the global eradication effort was a trivalent preparation comprising all three serotypes. When type 2 poliovirus was eliminated, many countries began immunizing only against types 1 and 3 poliovirus. As a consequence of this immunization strategy, population immunity to type 2 poliovirus declined. This has likely lead to the emergence of cVDPV2 in Pakistan, together with poor routine immunization coverage.

The resurrection of poliovirus type 2 highlights the difficulties in eradicating a pathogen using a vaccine that can readily mutate to cause the disease that it is designed to prevent. As wild type polioviruses are eliminated, the only remaining polio will be caused by the vaccine. If immunization is then stopped, as planned by WHO, there will likely be outbreaks of polio caused by cVDPV of all three serotypes. The solution to this conundrum is to switch to the inactivated vaccine until cVDPVs disappear from the planet.

Exacerbating the polio situation in Pakistan was the murder in the past week of nine immunization workers in several provinces. The Taliban, which carried out the executions, accused them of being spies. This accusation originates from the CIA operation in 2011 in which a Pakistani doctor ran an immunization program in Abbottabad in an attempt to obtain DNA samples from the Bin Laden family. As a result of this violence, immunization campaigns in Balochistan have been suspended. Coupled with the previous refusal of many parents to have their children immunized, this action makes it likely that poliovirus will spread more extensively in the country, making eradication even more difficult.

Poliovirus image courtesy of Jason Roberts.