Virologist Vincent Racaniello breaks down the first case of polio in the US in nearly a decade.
Eradication of poliomyelitis appears to be on track: types 2 and 3 polioviruses have been declared eradicated, and in the past 12 months there have been just 338 cases of type 1 polio in Afghanistan and Pakistan. But there have also been 491 cases of polio caused by the type 2 Sabin vaccine. The development of a modified version of the type 2 vaccine component could improve this situation.
The oral poliovirus vaccines (OPV) developed by Albert Sabin have played a huge role in reducing cases of polio globally from 400,000 a year in 1980 to the current numbers. Their success, however, comes with a cost: they may in rare cases cause the disease they are designed to prevent. The three serotypes of OPV are taken orally and then reproduce in the intestines where they confer effective immunity to polio. During reproduction of the viruses in the intestine, the mutations originally selected by Sabin to eliminate the neurovirulence of the viruses are lost. Most immunized children shed vaccine revertants, and about 1 in 1.4 million vaccine recipients contract polio.
These vaccine revertants also circulate extensively throughout the human population, and may cause outbreaks of polio in areas where vaccine coverage drops. To address this problem, in 2016 WHO removed the type 2 component of poliovirus from OPV, which is responsible for most of the vaccine-associated cases. However vaccine-derived type 2 polioviruses continue to circulate even after this vaccine withdrawal and have caused a number of outbreaks. The response to control these outbreaks is to conduct mass immunizations with OPV type 2 – which re-introduces vaccine-derived polioviruses into the environment.
The solution might be to develop a more genetically stable strain of type 2 OPV. Such strains have been developed by leveraging advances in basic research on polioviruses that have been carried out since the 1980s. A new OPV2 strain (nOPV2) was developed by introducing three different types of changes in the OPV2 genome. First, mutations were introduced in the 5â€™-noncoding region of the viral RNA in the area of a single base that is a major attenuating mutation in OPV. These changes were designed to stabilize this region against reversion. Second, an RNA stem loop structure called the cre element, which is essential for viral RNA synthesis, was relocated from its original position in the genome to the 5â€™-noncoding region. This alteration should prevent RNA recombination that would replace the viral 5â€™-end with that of other enteroviruses, thereby removing the stabilizing changes. Finally, the RNA polymerase was modified so that it made fewer copying errors and had reduced recombination frequency.
The resulting nOPV2 was tested extensively in cells in culture and in experimental animals to demonstrate that the virus did not revert within the 5â€™-noncoding region, did not recombine with other enteroviruses, and maintained an attenuation phenotype in animals.
Based on these findings nOPV2 and another redesigned strain produced by codon-deoptimization were tested in a phase I trial. The adult volunteers, previously immunized with poliovirus vaccine, were housed in a containment facility to prevent environmental release of nOPV2. After oral administration of either vaccine, adults were monitored for symptoms, induction of immunity, and reversion of the virus to neurovirulence. The results indicated that the nOPV2s are safe, immunogenic, and do not revert to neurovirulence, while maintaining a stable 5â€™-noncoding region.
Pending ongoing phase 2 trials, nOPV2 is likely to be licensed for use in quelling outbreaks of type 2 vaccine-derived polio. It cannot be tested for efficacy because there are insufficient cases of polio anywhere to allow such a study. It is hoped that the excreted vaccines will not revert to neurovirulence and will circulate for a limited time in humans, as suggested by the preclinical data, thereby eliminating type 2 vaccine-induced polio. However, the numbers of subjects in the clinical trial have been small, and the selection pressure imposed by thousands of human guts might change this outcome. Viruses have been known before to defy our expectations.
Today, on World Polio Day, wild poliovirus type 3 has been declared eradicated by a commission of the World Health Organization. The last case of type 3 poliomyelitis was recorded in 2012 in Nigeria. Because wild poliovirus type 2 was declared eradicated in 2015, now only wild poliovirus type 1 continues to circulate, causing paralysis in Afghanistan and Pakistan.
Wondering why the eradication certificate (pictured) says ‘wild’ poliovirus, and not simply poliovirus? The reason is that bivalent oral poliovirus vaccine, containing types 1 and 3, continues to be used globally. After oral administration of this vaccine, vaccine-derived strains are excreted in the feces. Although wild poliovirus type 2 was declared eradicated in 2015, vaccine-derived type 2 poliovirus strains continue to circulate. These vaccine-derived viruses have so far in 2019 caused 102 cases of poliomyelitis.
In other words, we will not be able to declare that poliovirus is eradicated until we stop using the oral poliovirus vaccines. Use of the type 2 oral poliovirus vaccine was stopped in 2016, and WHO suggested that at least one dose of inactivated poliovirus vaccine (IPV) – containing all three serotypes – be included in immunization schedules. Lower IPV use than anticipated has led to continued circulation of vaccine-derived type 2 poliovirus. Compounding the problem is the use of OPV to control outbreaks of vaccine-derived paralysis, leading to introduction of more vaccine viruses into the environment.
Vaccine-derived type 1 poliomyelitis is quite rare, and so if we can vaccinate properly in Afghanistan and Pakistan, we will likely be able to eradicate this serotype. The solution to the problem of type 2 poliovirus will require a complete global switch to IPV, or the use of a new vaccine that cannot revert during replication in the gut and cause paralysis. Such vaccines are in development.
The TWiV team covers outbreaks of eastern equine encephalitis virus in the US and poliovirus in the Philippines, and explain how a chemokine induced by HIV-1 infection helps release more virus particles from cells.
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Show notes at microbe.tv/twiv
Cases of poliomyelitis have been reported in the Philippines 19 years after the country was declared free of the disease. The return of poliomyelitis to the country emphasizes the need to maintain high levels of immunization while polioviruses continue to circulate.
The global withdrawal of the Sabin type 2 poliovirus vaccine is a test of the feasibility of the plan, declared by the World Health Assembly in 1988, to eradicate all polioviruses.