In early June it was widely reported that the first case of poliomyelitis in 30 years had been identified in Venezuela (see this Tech Times report as an example). Fortunately these reports were incorrect, and Venezuela remains free of polio. Let€™s unpack exactly what happened.
In early June the Pan-American Health Organization reported that on 29 April 2018 a 34 month old Venezuelan child developed acute flaccid paralysis (AFP). AFP is defined as a sudden onset of paralysis/weakness in any part of the body of a child less than 15 years of age.
AFP has many causes, only one of which is poliovirus infection. About 50,000 cases of AFP are reported each year in India, even though polio was declared eradicated from that country in 2014.
AFP surveillance is used as part of the poliovirus eradication effort to identify cases of polio. When cases of AFP are detected, a stool sample is taken to determine if poliovirus is present. In the case of the Venezuelan child, Sabin poliovirus type 3 was isolated from the stool.
This child had not been previously immunized with Sabin vaccine, so why was the virus present in the stool? Sabin€™s poliovirus vaccines are taken orally €“ hence the name oral poliovirus vaccine (OPV). As in a natural poliovirus infection, Sabin€™s vaccines replicate in the intestinal tract and induce protective immunity there and in the bloodstream. Sabin produced these vaccine strains by passaging polioviruses in different animals and cells until viruses were obtained that no longer cause paralysis.
We now understand that recipients of OPV may excrete, within a few days, viruses that are more neurovirulent that the vaccine strains. 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.
Such reversion to neurovirulence of the Sabin OPV strains can cause polio in vaccine recipients or their contacts. For example, from 1961 to 1989 in the US there were an average of 9 cases (range, 1-25 cases) of vaccine-associated paralytic poliomyelitis (VAPP), or 1 VAPP case per 2.9 million doses of OPV distributed.
As wild type polioviruses are eliminated, most of the cases of polio are caused by the vaccine: in 2017, there were 96 cases of VAPP and 22 caused by wild type poliovirus.
Here is the crux of the matter: vaccine-derived polioviruses can circulate in humans for many years undetected. When polio immunization coverage drops, these circulating vaccine-derived polioviruses can cause outbreaks of poliomyelitis.
The combination of lack of immunization of the child, the finding of AFP and Sabin type 3 OPV in the stool led to the erroneous conclusion by many (including me!) that this was a case of VAPP.
Determination of the nucleotide sequence of the Sabin type 3 poliovirus isolated from the child€™s stool revealed it did not have the mutations known to cause VAPP.
How can this conclusion be made from the viral genome sequence?
As Sabin polioviruses replicate in the human intestine, are excreted, and spread in the population, they sustain genome mutations at a rate of about 1% per year. This mutation rate makes it possible to determine how long the viruses have been circulating in humans. Some of these mutations are known to restore the ability of the virus to cause paralysis. Examination of the genome of the virus isolated from the child indicated that is was very much like Sabin 3 poliovirus, and does not have the capacity to cause polio (I€™ve not seen the sequence myself, so I have to take the word of the Global Polio Eradication Initiative).
The Venezuelan child had never received any type of poliovaccine, and lived in an under-immunized community. A mass vaccination campaign, using Sabin types 1 and 3 poliovaccine, had been done a few weeks before the onset of AFP. The child likely acquired Sabin 3 poliovirus from that immunization campaign, which coincided with the development of AFP. Sabin polioviruses are isolated from thousands of individuals each year who have AFP, but they are not the causative agents. The actual cause of AFP will likely never be known.
Had this been a case of poliovirus type 3 VAPP in an under-immunized area, it would have been bad news. How could we ever stop vaccinating against polio if infections can occur 30 years after the declaration of eradication?
The fact that immunization rates have fallen in parts of Venezuela is the real story here. As long as we are using Sabin OPV, immunization rates must remain high, to protect against VAPP. Meanwhile, the transition to the use of inactivated poliovaccine must be done to eliminate the threat of VAPP. As long as we use Sabin OPV, we cannot eradicate poliovirus.
Hmm… I’m skeptical of your conclusions, Vince. We know from Phil Minor’s classic work that OPV strains evolve rapidly in vaccinated individuals, as determined by the genome sequences of viruses isolated from their stool following vaccination. Isn’t it possible (even likely?) that within this unfortunate child, the OPV that he acquired from the recent vaccination campaign evolved into two divergent populations: the harmless intestinal one that was re-isolated from his stool and sequenced, and a neurotropic one that invaded his neural tissue and caused the AFP? We need to know the sequence of virus isolated from a motor neuron biopsy (!).
Thanks for this post Vincent! This has been an interesting story to follow as it develops. It is certainly reassuring that this case of AFP was not a result of the reintroduction of wild type poliovirus or a new epidemic of vaccine derived poliovirus in the Western hemisphere. However, it is my understanding of the reports that neither PAHO nor the WHO has ruled out VAPP. The PAHO epidemiological update from June 15 states that final classification of the case is pending, particularly whether it is vaccine associated or not. While it is true that VAPP cases often have evidence of mutations in the virus relative to OPV (as assessed in the stool), Kew et al. have reported that this is not always the case (Annual Review of Microbiology 59:587, 2005). I suspect the whole genome has been sequenced at this point, but I think the initial designation of wild type vs. VDPV vs. “other” is strictly based on the number of mutations in VP1, as opposed to reversion of specific mutations.
From my limited reading on the subject, it seems that the diagnosis of VAPP is made more on clinical and epidemiological criteria. See for example, http://www.who.int/vaccine_safety/initiative/tools/polio_vaccine_rates_information_sheet.pdf. This case appears to be a little unusual in that OPV3 was found in the stool, but there was no recent history of vaccination in the case. However, VAPP case definitions sometimes do allow for the possibility of infection from recently vaccinated individuals in close contact with the AFP case.
Pingback: Venezuela is still polio-free - Virology