Dreaming of inactivated poliovirus vaccine

26 February 2009

dreamingThe World Health Organization’s global polio eradication effort uses the live, attenuated poliovirus vaccines developed by Albert Sabin. When the eradication program was announced in 1988, the goal was to eliminate global poliomyelitis, then cease immunization with poliovirus at some point in the future. In 2002 an outbreak of polio in the Dominican Republic sent a warning that this goal might not be possible. Twenty-one cases of paralytic polio were caused by a vaccine-derived poliovirus strain (VDPV). Although it had been known since the 1960s that vaccine viruses excreted by vaccinees are neurovirulent revertants, their transmission potential was unknown.

The outbreak in the Dominican Republic, and several others that were subsequently identified, made it clear that VDPV strains posed a threat to the plan to cease polio immunization. In the worst case scenario, VDPV strains would continue to circulate after vaccination had stopped, endangering the growing number of non-immune individuals. Alan Dove and I suggested, in a 1997 Science article, that it might be prudent for WHO to switch to using the inactivated poliovirus vaccine, IPV, which cannot replicate in the recipient. Once OPV usage ended, the levels of circulating VDPVs would decrease until they no longer could trigger an outbreak. Careful monitoring of VDPV in sewage would indicate when it would be safe to stop immunization with IPV.

In early 2001 I spoke at a conference on disease eradication in Washington, DC, sponsored by the Institute of Medicine. The meeting was chaired by Joshua Lederberg, and attended by the directors of polio immunization programs from many countries. I gave a presentation in which I emphasized the need to switch from OPV to IPV to avoid the problem of circulating VDPVs. This proposal received a mixed response, but I recall in particular the comments of D.A. Henderson, the architect of smallpox eradication, who said:

So, we have then say 8 years or 7 years, whatever it is to gear up to the vaccine, then another 10 years in using the inactivated vaccine. This is just totally unrealistic. We are not going to have the financial support globally for this. 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.

I was surprised at the decisiveness of his comments, but after all, someone who has eradicated smallpox is very sure of himself.

Now WHO has now come full circle, as discussed in the Science article cited below. They agree that a transition to IPV is needed, and are looking into new ways to produce and deliver the vaccine.

And D.A. Henderson also agrees that a switch to IPV is needed. I guess I wasn’t dreaming after all.

A. W. Dove (1997). The Polio Eradication Effort: Should Vaccine Eradication Be Next? Science, 277 (5327), 779-780 DOI: 10.1126/science.277.5327.779

L. Roberts (2009). POLIO ERADICATION: Rethinking the Polio Endgame Science, 323 (5915), 705-705 DOI: 10.1126/science.323.5915.705

  • ET

    So, does he acknowledge that your logic was valid and idea sound in an email? Or when someones hubris is exposed, do they just try to forget that it ever happened at all?

  • http://www.virology.ws profvrr

    Standard protocol, unfortunately, is to ignore previous errors. I
    would not expect that he would remember who I am, nor what I said at
    the meeting. And I certainly did not expect an email. But see
    http://www.dovdox.com for further elaboration of the situation.

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    Das Institut kündigte an, die Fehlbuchungen innerhalb von 48 Stunden wieder rückgängig zu machen. “Die Kunden werden natürlich nicht die Konsequenzen dieses Vorfalls tragen”, hieß es bei BNP Paribas. Auch wer durch die Abbuchungen in die roten Zahlen gerutscht sei, müsse keine Zusatzkosten durch Zinsen befürchten. Wie viel Geld fälschlicherweise den Besitzer wechselte, wollte die Bank zunächst nicht sagen. Auch zur Ursache des Computerfehlers gab es keine Angaben.

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    Die Spanier dürften damit durchschnittlich zwischen 35 und 40 Euro pro Aktie hingelegt haben. Inzwischen ist der Kurs der Erste Bank an der Börse eingebrochen. Am Montagnachmittag kostete das Papier 7,46 Euro

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  • Mambo

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  • Bruce

    I just want to know that anyone accepts ur logic and anyone praised you for this..Because still i have doubt in this..
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  • Brian Hanley

    I am pretty familiar with the smallpox eradication effort, and I completely understand why Henderson said what he did. Smallpox was almost not eradicated, but there were many factors that helped this to happen, foremost among them that smallpox has no known subclinical manifestations that do not cause disfigurement. Polio, under normal circumstances with no vaccine is approximately 95% subclinical manifestation with little apparent disease. That means that people can be infected with, and shed the virus with no clinical indications that they are doing so.

    Smallpox is different than most viral diseases in that immunity to the vaccine provides 100% sterilizing immunity to the virus, and there is no disease transmission. Most vaccines result in a bell curve of titers and some level of circulation of the disease in subclinical form. I do not have a curve of the subclinical manifestation of polio after trivalent vaccine inoculation, but clearly, it is happening. Subclinical illness potential is 100% in populations vaccinated using killed virus vaccines like IPV. Since IGA is what combats polio in the gut, and IPV is a injected, it will produce primary titers of IgG, and those titers will be lower than after infection with polio, which will guarantee that to achieve more complete immunity to the disease will require subclinical infection with the virus. That means that subclinical polio will continue to circulate even after IPV is used. It will circulate at higher levels because killed vaccine produces lower titers.

    The problem with polio in Africa is twofold. First, it is possibly reverting, although it is very doubtful that it reverts in every case of live vaccine. That brings us to the second problem, which is sanitation. That part of the world has terrible sanitation, and that is how revertants (if they are revertants at all, and not original virus strains that continued to circulate) are spread.

    But that brings us to the third problem, which is the question of where the polio came from. There is an assumption that it had to come from the trivalent vaccine because it is presumed that after administration of the vaccine subclinical illness cannot occur in humans and the virus cannot reproduce and spread. But I am certain that this fundamental assumption is not correct. And in an environment in which fecal oral transmission is a norm, the virus can stay alive for generations without being noticed.

  • http://www.virology.ws profvrr

    Henderson's view was based on several factors, including the high cost
    of IPV and the lack of experience with this vaccine in developing
    countries. With respect to vaccine revertants, they have been shown to
    circulate even in countries with excellent sanitation (USA). The type
    2 polio in Nigeria is clearly vaccine derived – a fact that can be
    deduced by sequence analysis of viral isolates. This information shows
    that the type 2 virus is not wild virus.

  • Brian Hanley

    We do have experience with other such vaccines, for instance, measles in those regions. Net vaccination rate (efficacy fraction x fraction vaccinated) is around 50%.

    Regarding revertants, ok, however, I think the argument stands that an old revertant strain could circulate in the population after elimination of live vaccine. There is also another method of working on revertants, and that is to change the attenuated strain to have more critical mutations.

    There is yet another strategy, and that is to make a live recombinant vaccine with a different virus expressing the important proteins of polio. This method would be the safest and most effective.

  • Brian Hanley

    (This is from my own unpublished metanalysis of measles vaccine coverage.)
    Cite Location Efficacy Coverage Efficacy Coverage Net Net coverage
    1 dose % 1 dose % 2 dose % 2 dose % coverage deficit/overage

    1 Romania 89.0% 52.0% 96.0% 6.0% 52.0% -38.0%
    2 Masivingo 73.0% 75.0% 54.8% -35.3%
    Zimbabwe
    3 Mashonaland 84.9% 67.6% 57.4% -32.6%
    Zimbabwe
    4 Harare 68.0% 85.0% 57.8% -32.2%
    Zimbabwe
    5 Singapore 97.8% 93.0% 91.0% 1.0%
    6 Duisburg 98.1% 25.0% 99.4% 70.4% 94.5% 4.5%
    Germany
    7 Incheon 88.8% 7.0% 98.0% 90.8% 95.2% 5.2%
    Korea
    8 Pennsylvania 98.0% 3.9% 98.6% 94.9% 97.4% 7.4%
    USA
    Table 1 – Survey of vaccine efficacy and net vaccine coverage with eradication deficit.

    References
    1. Hennessey, Karen A. et al. Measles epidemic in Romania, 1996-1998: assessment of vaccine effectiveness by case-control and cohort studies. American Journal of Epidemiology 150, 1250-1257 December 1 (1999).
    2. Mudzamiri, W S, Peterson, D E, Marufu, T, Biellik, R J & L'Herminez, M. Measles vaccine efficacy in Masvingo district, Zimbabwe. Central African Journal of Medicine 42, 195-197 July (1996).
    3. Uyirwoth, G P. Measles in Mashonaland Central Province: Zimbabwe. East Africa Medical Journal 70, 455-459 July (1993).
    4. Mahomva, A I, Moyo, I M & Mbengeranwa, I O. Evaluation of a measles vaccine efficacy during a measles outbreak in Mbare, City of Harare Zimbabwe. Central African Journal of Medicine 43, 254-256 September (1997).
    5. Ong, G, Rasidah, N, Wan, S & Cutter, J. Outbreak of measles in primary school students with high first dose MMR vaccination coverage. Singapore Medical Journal 48, 656 661 (2007).
    6. Wichmann, O et al. Large measles outbreak at a German public school, 2006. Pediatric Infectious Disease Journal 26, 782-786 September (2007).
    7. So, Jae Sung, Go, Un Yeong, Lee, Dong Han, Park, Koang Suk & Lee2, Jong Koo. Epidemiological investigation of a measles outbreak in a preschool in incheon, Korea, 2006. J Prev Med Pub Health 41, 153-158 May (2008).
    8. Yeung, Lorraine F. et al. A limited measles outbreak in a highly vaccinated US boarding school. Pediatrics 116, 1287-1291 December (2005).

  • Brian Hanley

    Well, that didn't work. Formatting was lost. Trying again.
    (This is from my own unpublished metanalysis of measles vaccine coverage.)
    Cite _Location Efficacy __Coverage _Efficacy __Coverage _Net _____Net coverage
    ____________1 dose % _1 dose % __2 dose % __2 dose % _coverage _deficit/overage

    1 _Romania ___89.0%___52.0%____96.0%____6.0%____52.0%____-38.0%
    2 _Masivingo__73.0%___75.0%_____________________54.8%____-35.3%
    ___ Zimbabwe
    3 _Mashonaland 84.9%___67.6%_____________________57.4%____-32.6%
    __Zimbabwe
    4 _Harare _____68.0%___85.0%_____________________57.8%____-32.2%
    __Zimbabwe
    5 _Singapore ___97.8%___93.0%_____________________91.0%______1.0%
    6 _Duisburg ____98.1% ___25.0%___99.4%___70.4%_____94.5%______4.5%
    __Germany
    7 _Incheon_____88.8%____7.0%___98.0%___90.8%_____95.2%______5.2%
    __Korea
    8 _Pennsylvania_98.0%____3.9%___98.6%___94.9%_____97.4%_______7.4%
    __USA
    Table 1 – Survey of vaccine efficacy and net vaccine coverage with eradication deficit.

    References
    1. Hennessey, Karen A. et al. Measles epidemic in Romania, 1996-1998: assessment of vaccine effectiveness by case-control and cohort studies. American Journal of Epidemiology 150, 1250-1257 December 1 (1999).
    2. Mudzamiri, W S, Peterson, D E, Marufu, T, Biellik, R J & L'Herminez, M. Measles vaccine efficacy in Masvingo district, Zimbabwe. Central African Journal of Medicine 42, 195-197 July (1996).
    3. Uyirwoth, G P. Measles in Mashonaland Central Province: Zimbabwe. East Africa Medical Journal 70, 455-459 July (1993).
    4. Mahomva, A I, Moyo, I M & Mbengeranwa, I O. Evaluation of a measles vaccine efficacy during a measles outbreak in Mbare, City of Harare Zimbabwe. Central African Journal of Medicine 43, 254-256 September (1997).
    5. Ong, G, Rasidah, N, Wan, S & Cutter, J. Outbreak of measles in primary school students with high first dose MMR vaccination coverage. Singapore Medical Journal 48, 656 661 (2007).
    6. Wichmann, O et al. Large measles outbreak at a German public school, 2006. Pediatric Infectious Disease Journal 26, 782-786 September (2007).
    7. So, Jae Sung, Go, Un Yeong, Lee, Dong Han, Park, Koang Suk & Lee2, Jong Koo. Epidemiological investigation of a measles outbreak in a preschool in incheon, Korea, 2006. J Prev Med Pub Health 41, 153-158 May (2008).
    8. Yeung, Lorraine F. et al. A limited measles outbreak in a highly vaccinated US boarding school. Pediatrics 116, 1287-1291 December (2005).

  • http://www.virology.ws profvrr

    All your points are correct. Your idea for a novel vaccine would avoid
    the problems of reversion. Unfortunately few companies are willing to
    invest in developing a new polio vaccine with the disease nearly
    eradicated. It's a sad fact that economics drives vaccine development.

  • Brian Hanley

    Yes, too much so. But it isn't necessary for such a vaccine to be commercialized to use it in the end stages of eradication in Africa. WHO could fund it, and handle the vaccine distribution. After all, people like Yilma act as the practical repository for the rinderpest vaccine that is used in Africa in animals. So could the Gates foundation fund it.

    Such a vaccine could be developed in an academic lab and proved through to Rhesus studies in 3-4 years for less than $1MM. A crash program could do it in 1 year. The reason to bring in commercial outfits is when you need huge volumes and to make use of their distribution channels. That wouldn't be necessary or useful in this case. Considering the importance, and the amount of money spent on other things, it should be done.

  • http://www.virology.ws profvrr

    The Polio Research Committee of the Global Polio Eradication
    Initiative is funding work to produce a poliovirus VLP-like vaccine. I
    say VLP like because some viral RNA will be present, but it will lack
    sequences encoding the capsid region. The capsid proteins will be
    provided by a packaging cell line. See
    http://www.polioeradication.org/content/poliopi….
    I'm not sure this is the best way to go but at least it's a start.
    Anyone interested in developing alternative polio vaccines can apply
    for a research grant. Presumably the best leads will be pushed further
    by the Initiative.

  • Brian Hanley

    Thanks. Sent an email off to a guy who trained me a few years ago. Maybe something will come of it.

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