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VDPV

WHO will switch to type 2 inactivated poliovirus vaccine

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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.

Poliovirus type 2 returns

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polio-immunizationThe global battle to eradicate poliomyelitis is already 9 years behind schedule. To make matters worse, type 2 poliovirus, which was declared eradicated in 1999, has returned.

There are three serotypes of poliovirus, each of which causes poliomyelitis. The vaccine used by WHO in the global eradication effort is a trivalent preparation comprising all three serotypes. When type 2 poliovirus was eliminated, many countries began using monovalent type 1 and type 3 vaccines: one vaccine for type 1 and another for type 3. As a consequence of this immunization strategy, population immunity to type 2 poliovirus declined. But if type 2 poliovirus was eradicated, where has it come from?

It came from the poliovirus vaccine.

The trivalent vaccine that is used in the eradication effort is an infectious vaccine. The vaccine is ingested, the viruses replicate in the intestine, and immunity develops. Viruses of all three serotypes undergo genetic changes during replication in the alimentary tract. As a consequence, the vaccine recipient excretes neurovirulent polioviruses. These so-called vaccine-derived polioviruses (VDPV) can cause outbreaks of poliomyelitis in non-immune people, as described in Polio among the Amish.

The outbreak of type 2 poliovirus in Nigeria began in 2006. There have been 126 cases of paralytic disease reported so far in 2009. Before 2003, the year that Nigeria began a boycott of polio immunization, the trivalent vaccine was used. Immunization resumed with monovalent types 1 and 3 vaccine in 2004. Therefore the source of the VDPV type 2 is most likely the trivalent vaccine used before 2003.

The resurrection of type 2 polio highlights the difficulties involved in using an infectious viral vaccine to eradicate the disease. In reality, type 2 poliovirus was not eradicated in 1999, because that virus was still present in the trivalent vaccine that was being used. Clearly the virus was still circulating in humans, despite the fact that no type 2 poliomyelitis was observed.

In response to the type 2 outbreak in Nigeria, trivalent vaccine is being used again. It’s not difficult to imagine that this will lead to another cycle of eradication and emergence of type 2 polio. What’s the solution to this apparently endless circle? Use inactivated poliovirus vaccine, which I’ve been dreaming about for some time.

Roberts, L. (2007). Vaccine-Related Polio Outbreak in Nigeria Raises Concerns Science, 317 (5846), 1842-1842 DOI: 10.1126/science.317.5846.1842

Roberts, L. (2009). Type 2 Poliovirus Back From The Dead in Nigeria Science, 325 (5941), 660-661 DOI: 10.1126/science.325_660

Jegede, A. (2007). What Led to the Nigerian Boycott of the Polio Vaccination Campaign? PLoS Medicine, 4 (3) DOI: 10.1371/journal.pmed.0040073

Polio among the Amish

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amishThe last outbreak of poliomyelitis in the United States occurred in 1979, when a type 1 strain imported from the Netherlands caused 13 paralytic cases among unvaccinated Amish communities in three states. Twenty years later, use of the live, attenuated poliovirus vaccine (OPV) was discontinued in the United States, and was replaced with the inactivated vaccine, IPV.  How do we explain the 2005 outbreak of polio in an Amish community in Minnesota?

The infant in this case was five months old when it was hospitalized for fever, irritability, bloody diarrhea, and recurrent infections. Vaccine-derived poliovirus (VDPV) type 1 was isolated from a stool specimen, but paralysis did not occur. VDPVs are excreted by individuals who receive OPV; they have been shown to circulate for long periods and cause outbreaks of paralytic disease in undervaccinated populations. Similar VDPVs were subsequently isolated from four other children in the same Amish community, none of whom were ill. A total of 8 out of  23 children tested had virologic or serologic evidence of type 1 poliovirus infection.

Sequence analysis of the VDPVs was used to estimate that the virus had probably circulated for 2 months in the community before infecting the infant. Such estimates are based on the known rate of sequence change in the poliovirus genome as it moves through the human population. The origin of the VDPV was not identified, despite extensive virological and serological studies of other communites in the US and Canada which might have had contact with the individuals in Minnesota. The source of the virus is probably a recipient of OPV outside of the US and Canada – these countries stopped using this vaccine in 2000 and 1995-96, respectively.

The infant was subsequently diagnosed with severe combined immunodeficiency, a disease characterized by defects in B and T cell immunity and frequent infections. Poliovirus was detected in her stool until January 2006, after which the immunodeficiency was corrected by bone marrow transplant and the virus was eliminated.

All previous outbreaks of poliomyelitis caused by VDVP were in undervaccinated communities in underdeveloped countries. The outbreak in Minnesota underscores the need to maintain high vaccination coverage: until OPV is replaced with IPV globally, circulating VDPVs pose a threat to unimmunized individuals. The outbreak is a harbinger of what could occur in countries where immunization with OPV is halted after the eradication of poliomyelitis. As the number of susceptible newborns increases, circulating VDVPs could spark an outbreak of poliomyelitis.  Another reason for switching to IPV rather than stopping immunization altogether.

James P. Alexander, Kristen Ehresmann, Jane Seward, Gary Wax, Kathleen Harriman, Susan Fuller, Elizabeth A. Cebelinski, Qi Chen, Jaume Jorba, Olen M. Kew, Mark A. Pallansch, M. Steven Oberste, Mark Schleiss, Jeffrey P. Davis, Bryna Warshawsky, Susan Squires, Harry F. Hull (2009). Transmission of Imported Vaccine‐Derived Poliovirus in an Undervaccinated Community in Minnesota The Journal of Infectious Diseases, 199 (3), 391-397 DOI: 10.1086/596052