virology blog
About viruses and viral disease
From the 22nd meeting of the European Society for Clinical Virology in Copenhagen, Vincent speaks with Thea, Heli, Kim, Caroline and Irma about big data and its increasing use in virology diagnostics, epidemiology, and public health.
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For the first time since April of 1955, recipients of poliovirus vaccine will no longer receive all three serotypes. This past Sunday the World Health Organization orchestrated a synchronized switch from trivalent to bivalent oral poliovirus vaccine (OPV) in 150 countries.
The reason for the switch is clear: type 2 poliovirus was declared eradicated last year, and the only remaining cases are cause by vaccine-derived type 2 polioviruses. After oral administration of poliovirus vaccine, the virus replicates in the intestine, conferring immunity to subsequent infection. In all recipients of the vaccine the viruses lose the mutations that make them safe for humans. Consequently a small number of recipients, and their contacts, contract poliomyelitis from the vaccine.
To prevent further cases of poliomyelitis caused by circulating vaccine-derived polioviruses, WHO planned a synchronized, global switch from trivalent OPV to bivalent OPV on 17Â 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.
My concern with this strategy is that type 2 vaccine-derived polioviruses continue to circulate. Whether they will continue to do so long enough to cause an outbreak of paralytic disease in the cohort of new infants that do not receive type 2 vaccine is a mattern of conjecture. In case there is an outbreak, monovalent type 2 oral poliovirus vaccine is being stockpiled by WHO. Of course, re-introduction of this vaccine will be accompanied by more circulating vaccine-derived poliovirus in the environment, and vaccine-associated disease, the very event WHO is trying to end with the trivalent to bivalent switch.
Type 3 poliovirus has not been isolated since 2012. Only type 1 poliovirus still causes outbreaks in two countries: Pakistan and Afghanistan. The inability to vaccinate in those countries, due to conflict, is delaying eradication. The recent killing of seven police officers who were protecting polio vaccinators by the Pakistani Taliban is an example of this difficulty.
Developing a great vaccine is not the only requirement for preventing infectious disease: you also have to be able to deploy it.
Image: Antibodies bound to poliovirus by Jason Roberts.
In 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.
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:Â 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.
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.
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.