Three countries endemic for poliovirus

poliovirusI cannot let September pass without noting that 34 years ago this month, I arrived at Columbia University to start my laboratory to do research on poliovirus (pictured). That virus is no longer the sole object of our attention – we are wrapping up some work on poliovirus and our attention has shifted elsewhere. But this is a good month to think about the status of the poliovirus eradication effort.

So far this year 26 cases of poliomyelitis have been recorded – 23 caused by wild type virus, and three caused by vaccine-derived virus. At the same time in 2015 there were 44 reported cases of polio – small progress, but, in the words of Bill Gates, the last one percent is the hardest.

One of the disappointments this year is Nigeria. It was on the verge of being polio-free for one year – the last case of type 1 poliovirus in Nigeria had been recorded in July of 2014. In August the government reported that 2 children developed polio in the Borno State. The genome sequence of the virus revealed that it had been circulating undetected in this region since 2011. Due to threats from militant extremists, it has not been possible for vaccination teams to properly cover this area, and surveillance for polioviruses has also been inefficient. The virus can circulate freely in a poorly immunized population, and as only 1% of infections lead to paralysis, cases of polio might have been missed.

The conclusion from this incident is that the declaration that poliovirus is no longer present in any region is only as good as the surveillance for the virus, which can never be perfect as all sources of infection cannot be covered.

Of the 26 cases of polio recorded so far in 2016, most have been in Afghanistan and Pakistan (9 and 14, respectively). It is quite clear that conflict has prevented vaccination teams from immunizing the population: in Pakistan, militants have attacked polio teams during vaccination campaigns.

Recently 5 of 27 sewage samples taken from different parts of the province of Balochistan in Pakistan have tested positive for poliovirus. Nucleotide sequence analysis revealed that the viruses originated in Afghanistan. The fact that such viruses are present in sewage means that there are still individuals without intestinal immunity to poliovirus in these regions. In response to this finding, a massive polio immunization campaign was planned for the end of September in Pakistan. This effort would involve 6000 teams to reach 2.4 million children. Apparently police will be deployed to protect immunization teams (source: ProMedMail).

The success of the polio eradication program so far has made it clear that if vaccines can be deployed, circulation of the virus can be curtailed. If immunization could proceed unfettered, I suspect the virus would be gone in five years. But can anyone predict whether it will be possible to curtail the violence in Pakistan, Afghanistan, and Nigeria that has limited polio vaccination efforts?

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’.

TWiV 353: STING and the antiviral police

On episode #353 of the science show This Week in Virology, the TWiVniacs discuss twenty-eight years of poliovirus shedding by an immunodeficient patient, and packaging of the innate cytoplasmic signaling molecule cyclic GMP-AMP in virus particles.

You can find TWiV #353 at

Shedding poliovirus for 28 years

Glass PoliovirusAn immunodeficient individual has been excreting poliovirus in his stool for 28 years. Such chronic excreters pose a threat to the poliovirus eradication program.

Since its inception in 1988 by the World Health Organization, the poliovirus eradication program has relied on the use of the infectious, attenuated vaccine strains produced by Albert Sabin. These viruses are taken orally, replicate in the intestine, and induce protective immunity. During replication in the gut, the Sabin strains lose the mutations that prevent them from causing paralysis. Nearly every individual who receives the Sabin vaccine strains excretes so-called vaccine-derived polioviruses (VDPVs) which are known to have caused outbreaks of poliomyelitis in under-immunized populations.

Immunocompromised individuals who produce very low levels of antibodies (a condition called agammaglobulinemia) are known to excrete VDPVs for very long periods of time – years, compared with months in healthy individuals. Seventy-three such cases have been described since 1962. These individuals receive the Sabin vaccine in the first year of life, before they are known to have an immunodeficiency, at which time they must receive antibodies to prevent them from acquiring fatal infections.

The most recently described immunocompromised patient was found to excrete poliovirus type 2 vaccine for 28 years (the time period is determined by combining the known rate of change in the poliovirus genome with sequence data on viruses obtained from the patient).  The VDPV is neurovirulent (causes paralysis in a mouse model), antigenically drifted, and excreted in the stool at high levels.

Because the polio eradication plan calls for cessation of vaccination at some future time, these immunocompromised poliovirus shedders pose a threat to future unimmunized individuals. The global number of such patients is unknown, and there is no available therapy to treat them – administration of antibodies does not clear the infection. The development of antivirals that could eliminate the chronic poliovirus infection is clearly needed (and ongoing). It will also be necessary to conduct environmental surveillance for the presence of VDPVs – they can be identified by properties that distinguish them from VDPVs produced by immunocompetent vaccine recipients.

While the WHO eradication plan now includes a shift to using inactivated (Salk) poliovaccine, this strategy would not impact the existing immunocompromised poliovirus shedders. Should a VDPV from these individuals cause an outbreak of polio in the post-vaccine era, it will be necessary to control the outbreak with Salk vaccine, or an infectious poliovirus vaccine that cannot revert to virulence during replication in the intestine. Polioviruses with a recoded genome are candidates for the latter type of vaccine.

Image credit: Jason Roberts

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.

India has been free of polio for three years

Poliovirus cutaway

Image credit: Jason Roberts

Three years ago today, on 13 January 2011, the last case of poliomyelitis was reported in India. This achievement represents a remarkable turnaround for a country where control of the disease had for years been extremely difficult. As recently as 2009 there were 741 confirmed cases of polio caused by wild-type virus in India. Being polio-free for three years is certainly a cause for celebration, but not for becoming complacent. Immunization efforts in India must not decline, because wild-type and vaccine-derived polioviruses continue to circulate and pose a threat to any unimmunized individual.

Wild polioviruses – those that have always been circulating in nature – continue to cause disease in Afghanistan and Pakistan, two countries close to India. Pakistan reported 58 polio cases in 2012, and 85 so far in 2013; for Afghanistan the numbers are 37 and 12. But distant countries can also transmit polio: recent outbreaks in the Horn of Africa and in Syria originated in Nigeria and Pakistan, respectively.

Perhaps a greater threat are vaccine-derived polioviruses. The Sabin poliovirus vaccines, which have so far been the mainstay of the polio eradication effort, comprise infectious viruses that are taken orally. Upon replication in the intestinal tract, the vaccine strains confer immunity to infection, but they also revert and become capable of causing paralysis. Such vaccine-derived polioviruses circulate and can cause outbreaks of polio. Because India has been using Sabin poliovirus vaccines intensely for many years, there is no doubt that vaccine-derived polioviruses are circulating in that country. If polio vaccine coverage drops, there will be outbreaks of polio caused by vaccine-derived strains. Even if wild polioviruses disappeared from the globe, as long as Sabin vaccines are used, vaccine-derived polioviruses will circulate. The solution to this conundrum is to switch to Salk’s inactivated poliovirus vaccine and wait for the Sabin-derived strains to disappear. This switch is now part of the WHO’s eradication plan (it wasn’t always), but it will not be easy: Salk vaccine must be injected, and therefore requires trained health care personnel; administering Sabin vaccine requires no special skills. But we cannot simply stop immunizing with Sabin vaccine – that is a recipe for outbreaks of polio.

According to the World Health Organization, being free of wild polio for three years means that the virus is probably no longer endemic in India. However, WHO does not certify individual countries as polio-free; rather it declares a WHO region polio-free when all countries in the Region have not reported a case of wild polio for 3 years in the face of highly active surveillance. The Americas, the Western Pacific, and European regions have been declared polio-free by WHO. India is part of the South-East Asia region, which also includes Bangladesh, Bhutan, Democratic People’s Republic of Korea, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, and Timor-Leste, none of which have reported a case of polio for 3 years. WHO will decide in March whether to declare this region polio-free. That would leave the regions of Africa and the Eastern Mediterranean as the last known reservoirs of wild poliovirus.