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.

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.

WHO assessment of experimental Ebola virus vaccines

The World Health Organization held a conference to assess the status of testing and eventual licensing of two candidate Ebola virus vaccines. The agenda and list of participants and the final report are available. I was interested in the following list of key expected milestones:

October 2014:
Mechanisms for evaluating and sharing data in real time must be prepared and agreed upon and the remainder of the phase 1 trials must be started

October–November 2014:
Agreed common protocols (including for phase 2 studies) across different sites must be developed

October–November 2014:
Preparation of sites in affected countries for phase 2 b should start as soon as possible

November–December 2014:
Initial safety data from phase 1 trials will be available

January 2015:
GMP (Good Manufacturing Practices) grade vaccine doses will be available for phase 2 as soon as possible

January–February 2015:
Phase 2 studies to be approved and initiated in affected and non-affected countries (as appropriate)

As soon as possible after data on efficacy become available:
Planning for large-scale vaccination, including systems for vaccine financing, allocation, and use.

I wonder how a phase 2 study will be conducted, the goal of which is to determine if it is effective and further evaluate its safety. Will this be done in west Africa, where protection against Ebola virus infection can be assessed? If so, will there be controls who receive placebo?

If indeed an Ebola virus vaccine is our best hope in limiting the current outbreak, it won’t be distributed for a while, according to the optimistic expectations of WHO – assuming all proceeds on time, and that the results are favorable.

TWiV 284: By the pricking of my thumbs, something wicked this way comes

On episode #284 of the science show This Week in Virology, the TWiV team discusses how skin scarification promotes a nonspecific immune response, and whether remaining stocks of smallpox virus should be destroyed.

You can find TWiV #284 at www.microbe.tv/twiv.

WHO report on human cases of avian influenza A(H7N9) infection

The World Health Organization has been publishing weekly reports on the avian influenza A(H7N9) outbreak which include the geographical location of each case, the cumulative number of cases, and the epidemiological curve. Go to this page at the WHO website for an archive of the weekly reports (there you will also find other useful information on the H7N9 outbreak). Images for report #3 of 24 April 2013 are reproduced below. Click each image for a larger view.

03_ReportWebH7N9Number_1
03_ReportWebH7N9Number_2
03_ReportWebH7N9Number_3

TWiV 229: Partly cloudy with a high of H7N9

On episode #229 of the science show This Week in Virology, Vincent, Rich, Dickson, and Alan review the current status of human infections with avian influenza H7N9 virus.

You can find TWiV #229 at www.microbe.tv/twiv.

TWiV 227: Lacks security and bad poultry

On episode #227 of the science show This Week in Virology, the complete TWiV team reviews the controversial publication of the HeLa cell genome, a missing vial of Guanarito virus in a BSL-4 facility, and human infections with avian influenza H7N9 virus.

You can find TWiV #227 at www.microbe.tv/twiv.

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.

H1N1 pandemic is over

The World Health Organization has declared the end of the pandemic caused by H1N1 influenza virus. According to Director-General Margaret Chan,

The world is no longer in phase 6 of influenza pandemic alert. We are now moving into the post-pandemic period. The new H1N1 virus has largely run its course.

As we enter the post-pandemic period, this does not mean that the H1N1 virus has gone away. Based on experience with past pandemics, we expect the H1N1 virus to take on the behaviour of a seasonal influenza virus and continue to circulate for some years to come.

According to the Director-General, levels and patterns of H1N1 transmission are now different from those observed during the pandemic. Out-of-season outbreaks are no longer being reported, and their intensity is similar to that seen during seasonal epidemics. In addition, multiple influenza viruses are being isolated in many countries, a pattern typical of many recent seasonal epidemics.

I take particular interest in what the Director-General believes did not happen:

This time around, we have been aided by pure good luck. The virus did not mutate during the pandemic to a more lethal form. Widespread resistance to oseltamivir did not develop. The vaccine proved to be a good match with circulating viruses and showed an excellent safety profile.

I continue to wonder why the Director-General, and many others, feel that influenza virus must change to a more lethal form. Although the four previous influenza pandemics occurred in multiple waves of increasing lethality, there is no evidence that they are a consequence of viral mutation. For example, the only virus available from the 1918 pandemic was rescued from an Alaskan influenza victim who was buried in permafrost in November of that year, when higher mortality was already evident. This makes it impossible to correlate any genetic changes in the virus with increased virulence. Viruses are available from different stages of the pandemics of 1957 and 1968, which also occurred in waves of increasing lethality, but to my knowledge the virulence studies have not been done.

I believe that a major selective force for viral evolution is the need to maintain efficient transmission among hosts. This may be achieved by any number of phenotypic changes, such as increases in stability and virion production. Changes in lethality might also lead to more effective transmission – for example, by inducing more severe coughing, the virus could be better transmitted among humans. But there is no genetic evidence that such changes have occurred during influenza virus pandemics.

How has the idea that influenza virus mutates to greater lethality permeated our popular culture? I don’t know the answer, but John Barry’s The Great Influenza is a prime suspect.

Pandemic quiz

The World Health Organization has declared that the world is now at the start of an influenza pandemic. WHO Director-General Dr. Margaret Chan said today:

I have conferred with leading influenza experts, virologists, and public health officials. In line with procedures set out in the International Health Regulations, I have sought guidance and advice from an Emergency Committee established for this purpose.

On the basis of available evidence, and these expert assessments of the evidence, the scientific criteria for an influenza pandemic have been met.

I have therefore decided to raise the level of influenza pandemic alert from phase 5 to phase 6.

The world is now at the start of the 2009 influenza pandemic.

The illustration below will need to be modified for the next edition of my textbook. This week’s pop quiz: What should be the origin of the 8 RNA segments of the 2009 H1N1 pandemic strain? Here is a larger version of the image if you subscribe to the adage that a picture is worth a thousand words.

influenza-pandemics