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neurovirulence

TWiV 931: Driven to immunodistraction

28 August 2022 by Vincent Racaniello

TWiV reviews the genetic characterization of a new strain of type 2 oral polio vaccine and its implications for eradication, and how a polymorphism in humans comprising a single amino acid change in an antibody molecule regulates vaccine elicitation of broadly neutralizing antibodies against influenza virus HA.

Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Kathy Spindler, and Brianne Barker

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Show notes at microbe.tv/twiv

Filed Under: This Week in Virology Tagged With: broadly neutralizing antibody, influenza virus, neurovirulence, nOPV2, poliovirus, vaccine, viral, virology, virus, viruses, wastewater

A genetically stable attenuated poliovirus vaccine

13 May 2021 by Vincent Racaniello

png_polio_gpei_310

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 5’-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 5’-noncoding region. This alteration should prevent RNA recombination that would replace the viral 5’-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 5’-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 5’-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.

Filed Under: Basic virology, Information Tagged With: attenuated vaccine, genetic stability, neurovirulence, OPV, poliovirus, recombination, reversion, Sabin, viral, virology, virus, viruses

TWiV 540: Wascally wiruses

24 March 2019 by Vincent Racaniello

The TWiVstars reveal the diversity of herpes simplex virus type 2 in a neonatal population, and parallel adaptation of rabbits in three countries to myxoma virus.

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Filed Under: This Week in Virology Tagged With: adaptation, comparative genomics, genome sequence, herpes simplex virus, herpes simplex virus type 2, human herpesvirus 2, minor variants, myxoma virus, neonatal, neonate, neurovirulence, parallel evolution, poxvirus, rabbit, viral, viral spread, virology, virus, viruses

TWiV 517: Just in time for Halloween

28 October 2018 by Vincent Racaniello

Brianne and Vincent tackle two studies that utilize infectious viruses to examine zoonotic potential of Bombali virus, a new ebolavirus from an insectivorous species in Sierra Leone, and a human mumps-like virus from an African flying fox in DRC.

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Show notes at microbe.tv/twiv

Filed Under: This Week in Virology Tagged With: Africa, asymptomatic infection, bat virus, bat-borne mumps virus, Bombali virus, ebolavirus, fruit bat, insectivorous bat, mumps virus, neurotropism, neurovirulence, viral, virology, virus, viruses, zoonosis, zoonotic potential

TWiV 371: Sympathy for the devil

10 January 2016 by Vincent Racaniello

TWiVOn episode #371 of the science show This Week in Virology, the TWiVologists discuss the finding of a second transmissible cancer in Tasmanian devils, and development of new poliovirus strains for the production of inactivated vaccine in the post-eradication era.

You can find TWiV #371 at www.microbe.tv/twiv.

Filed Under: This Week in Virology Tagged With: attenuation, circulating vaccine-derived poliovirus, eradication, inactivated poliovaccine, IPV, microsatellite DNA, neurovirulence, OPV, oral poliovaccine, poliovirus, reversion, Tasmanian devil, Tasmanian devil facial tumor, transmissible cancer, vaccine seed strain, viral, virology, virus, viruses

Poliovirus vaccine safety

8 April 2010 by Vincent Racaniello

Albert SabinThe contamination of the rotavirus vaccine Rotarix with porcine circovirus 1 DNA was revealed by deep sequencing. The same technique was also used to demonstrate that oral poliovirus vaccine does not contain viruses that can cause poliomyelitis.

The oral poliovirus vaccine strains developed by Albert Sabin (pictured) were licensed in the United States in 1962, and over the next 37 years immunization with these vaccines lead to the eradication of poliomyelitis in this country. During that period, the vaccine was responsible for 5-10 cases of poliomyelitis each year, either in recipients of the vaccine or in their contacts. Some of these individuals have sued the manufacturers of the vaccine, claiming that they made a defective product.

OPV contains three different poliovirus strains which were selected by Sabin because they do not cause poliomyelitis. We call such vaccine strains avirulent or attenuated. The mutations in the genetic information of the virus that prevent the development of paralysis have been identified. Unfortunately, these mutations are unstable. After oral administration, OPV replicates in the intestinal tract. During this phase the vaccine viruses undergo genetic change and eventually lose the mutations that made them avirulent. As a consequence, nearly every infant who receives OPV sheds in the feces polioviruses that are significantly more neurovirulent than those that were ingested.

Vaccine-associated poliomyelitis is caused by vaccine revertants that accumulate in the alimentary tract of immunized individuals. These neurovirulent viruses arise not because the vaccine is improperly prepared, but as a consequence of mutation during replication in the intestine. Proving this point to lay juries has been difficult. Now deep sequencing of poliovirus vaccine can show whether or not vaccine preparations are contaminated with neurovirulent viruses.

Deep sequence analysis of OPV manufactured by Bharat Biotech was done to detect mutations associated with neurovirulence. There are four mutations in the genome of type 1, two in the genome of type 2, and three in the genome of type 3 that are important for the attenuated property of the vaccine. The base present at each of these positions in the neurovirulent wild type viruses, and in the vaccine strains, is shown in the table.

Determinants of attenuation

The results of sequence analysis show that the Bharat vaccine does not contain any of the ‘wild type’ bases at these nine positions. Any vaccine-associated poliomyelitis associated with this vaccine is not a consequence of faulty production, but the fact that vaccine strains mutate during replication in the human gut.

There have been many lawsuits involving vaccine-associated poliomyelitis in which plaintiffs claim that the OPV was incorrectly manufactured, leading to a product of unacceptably high neurovirulence. Deep sequencing analysis of these lots of vaccine could have resolved this claim in a way that a lay jury could understand.

Filed Under: Basic virology, Information Tagged With: 454, mutation, neurovirulence, OPV, poliovirus, reversion, Sabin, vapp, viral, virology, virus

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by Vincent Racaniello

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