Virologist Vincent Racaniello breaks down the first case of polio in the US in nearly a decade.
At Aarhus University in Denmark, Vincent speaks with Trine Mogensen, SÃ¸ren Paludan, Ole SÃ¸gaard, and Madalina Carter-Timofte about their careers and their work on sensing herpesviral DNA, immunodeficiencies that predispose to severe viral infections, and the path to a cure for HIV/AIDS.
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Show notes at microbe.tv/twiv
Polio returns to Nigeria, Zika virus spreads in Miami, and virus infection of plants attracts bumblebees for pollination, from the virus gentlepeople at TWiV.
You can find TWiV #400 at microbe.tv/twiv, or listen below.
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On episode #373 of the science show This Week in Virology,Â Vincent speaks with Julius about his long career in virology, including his crucial work as part of the team at the University of Pittsburgh that developed the Salk inactivated poliovirus vaccine.
You can find TWiV #373 at microbe.tv/twiv. Or you can watch the video below.
In four months, 155 countries will together switch from using trivalent to bivalent oral poliovirus vaccine. Will this changeÂ lead to more cases of poliomyelitis?
There are three serotypes of poliovirus, each of which can cause paralytic poliomyelitis. The Sabin oral poliovirus vaccine (OPV), which has been used globally by WHO in the eradication effort, is a trivalent vaccine that contains all three serotypes.
In September 2015 WHO declared that wild poliovirus type 2 has been eradicated from the planet – no cases caused by this serotype had been detected since November 1999. However, in 2015, there were 9 cases of poliomyelitis caused by the type 2 vaccine. For theseÂ reasons WHO decided to removeÂ the type 2 Sabin strain fromÂ OPV, and switch from trivalent to bivalent vaccine in April 2016.
AfterÂ OPV is ingested, the viruses replicate in the intestinal tract, providing immunity to subsequent infection. During replication in the intestine, the vaccine viruses lose the mutations that prevent themÂ from causing paralysis. Everyone who receives OPV sheds these revertant viruses in the feces. In rareÂ cases (about one in 1.5 million) the revertant virusesÂ cause poliomyelitis in the vaccine recipient (these cases are called VAPP for vaccine-associated paralytic poliomyelitis). Vaccine-derived polioviruses can also circulate in the human population, and in under-vaccinated populations, they can cause poliomyelitis.
There were 26 reported cases of poliomyelitis caused by the type 1 or type 2 vaccine viruses in 2015. Nine cases of type 2 vaccine-associated polio were detected in four countries: Pakistan, Guinea, Lao Peopleâ€™s Democratic Republic, and Myanmar. RemovingÂ theÂ type 2 strain fromÂ OPVÂ will eliminateÂ vaccine-associated poliomyelitis in recipients caused by this serotype. WhenÂ the US switched from OPV to the inactivated poliovaccine (IPV) in 2000, VAPP was eliminated.
The problem with the trivalent to bivalent switch is thatÂ vaccine-derived type 2 poliovirus is likelyÂ still circulating somewhere on Earth.Â The last two reported cases of type 2 vaccine-associated polio in 2015 wereÂ reportedÂ in Myanmar in October. The viruses isolated from these cases were genetically related to strains that had been circulating in the same village in April of the thatÂ year. In other words, type 2 vaccine-derived strains have been circulating for an extended period of time in Myanmar; they have been known to persist for years elsewhere. If these virusesÂ continue to circulate past the time that immunization against type 2 virus stops, they could pose a threat to the growing numbers of infants and children who have not been immunized against this serotype.
Eventually as type 3, and then type 1 polioviruses are eradicated, it will also be necessary to stop immunizing with the respective Sabin vaccine strains. The switch from trivalent to bivalent vaccine in April 2016 is essentially an experiment to determineÂ if it is possible to stop immunizing with OPV without placing newborns at risk fromÂ circulating vaccine-derived strains.
Over 18 years ago Alan Dove and I argued that the presence of circulating vaccine-derived polioviruses made stopping immunization with OPVÂ a bad idea. We suggested instead aÂ switch from OPV to IPV until circulating vaccine-derived viruses disappeared. At the time, WHO disagreeed, but now they recommend that all countries deliver at least one dose of IPV as part of their immunization program. Instead of simply removing the Sabin type 2 strain from the immunization programs of 155 countries, it should be replaced with the inactivated type 2 vaccine. ThisÂ change would maintain immunity to this virus in children born after April 2016. Such aÂ synchronized replacementÂ is currently not in the WHO’s polio eradication plans. I hope that their strategy is the right one.
The Sabin infectious, attenuated poliovirus vaccines are known to cause vaccine-associated paralysis in a small number of recipients. In contrast, the Salk inactivated vaccine does not cause poliomyelitis.Â Why areÂ the Sabin vaccines still used globally? The answer to this questionÂ requires a brief visit to the history of poliovirus vaccines.
The inactivated poliovirus vaccine (IPV) developed by Jonas Salk was licensed for use in 1955. This vaccine consists of the three serotypes of poliovirus whose infectivity, but not immunogenicity, is destroyed by treatment with formalin. When prepared properly, IPV does not cause poliomyelitis (early batches of IPV were not sufficiently inactivated, leading to vaccine-associated outbreaks of polio, the so-called Cutter incident). From 1955 to 1960 cases of paralytic poliomyelitis in the United States dropped from 20,000 per year to 2,500.
While Salk’s vaccine was under development, several investigators pursued the production of infectious, attenuated vaccines as an alternative. This approach was shown to be effective by Max Theiler, who in 1937 had madeÂ an attenuated vaccine against yellow fever virus by passage of the virulent virus in laboratory mice. After many passages, the virus no longer caused disease in humans, but replicated sufficiently to induce protective immunity. Albert Sabin capitalized on these observations and developed attenuated versions of the three serotypes ofÂ poliovirus by passage of virulent viruses in different animals and cells. In contrast to Theiler’s yellow fever vaccine, which was injected, Sabin’s poliovirus vaccines were designed to be taken orally – hence the name oral poliovirus vaccine (OPV). As inÂ a natural poliovirus infection, Sabin’sÂ vaccinesÂ would replicate in the intestinal tract and induce protective immunity there and in the bloodstream.
Sabin began testing his attenuated vaccines in humans in 1954. By 1957 there was evidence that the virus that was fed to volunteers was not the same as the virus excreted in the feces. As Sabin writes:
It was evident, however, that as in the young adult volunteers, the virus in some of the stool specimens had a greater neurovirulence than the virus originally swallowed in tests in monkeys.
What Sabin did not know was whether the change in neurovirulence of his vaccine strains constituted a threat to the vaccine recipients and their contacts, a question that could only be answered by carrying out larger clinical trials. Many felt that such studies were not warranted, especially considering the success of IPV in reducing the number of paralytic cases. Sabin notes that his friend Tom Rivers, often called the father of American virology, told him to ‘discard the large lots of OPV that I had prepared into a suitable sewer’.
Despite the opposition to further testing of OPV in the US, others had different views. An international committee of theÂ World Health Organization recommended in 1957 that larger trials of OPV should be carried out in different countries. Sabin’s type 2 vaccine was given to 200,000 children during an outbreak of polio in Singapore in 1958, and follow-up studies revealed no safety problems. In Czechoslovakia 140,000 children were given OPV and subsequent studies revealed that the virus spread to unimminized contacts but did not cause disease.
Perhaps the most important numbers came from trials of OPV in the Soviet Union. Sabin had been born in Russia and had close contacts with Soviet virologists, including Mikhail Chumakov, director of the Poliomyelitis Research Institute in Moscow. Chumakov was not satisfied with the results of IPV trials in his country and asked Sabin to send him OPV for testing. By the end of 1959 nearly 15,000,000 people had been given OPV in different parts of the Soviet Union with no apparent side effects. Dorothy Horstmann, a well known virologist at Yale University, was sent to the Soviet Union to evaluate the outcome of the trials. Horstmann writes:
It was clear that the trials had been carefully carried out, and the results were monitored meticulously in the laboratory and in the field. By mid-1960 approximately 100 million persons in the Soviet Union, Czechoslovakia, and East Germany had received the Sabin strains. Of great importance was the demonstration that the vaccine was safe, not only for the recipients, but for the large numbers of unvaccinated susceptible who must have been exposed as contacts of vaccines.
The results obtained from these trials in the Soviet Union convinced officials in the US and other countries to carry out clinical trials of OPV. In Japan, Israel, Chile, and other countries, OPV was shown to be highly effective in terminating epidemics of poliomyelitis. In light of these findings, all three of Sabin’s OPV strains were approved for use in the US, and inÂ 1961-62Â they replaced IPV for routine immunization against poliomyelitis.
As soon as OPV was used in mass immunizations in the US, cases of vaccine-associated paralysis were described. Initially Sabin decried these findings, arguing that temporal association of paralysis with vaccine administration was not sufficient to implicate OPV. He suggestedÂ that the observed paralysis was caused by wild-type viruses, not his vaccine strains.
A breakthrough in our understanding of vaccine-associated paralysis came in the early 1980sÂ when the recently developed DNA sequencing methods were used to determine the nucleotide sequences of the genomes of the Sabin type 3 vaccine, the neurovirulent virus from which it was derived, and a virus isolated from a child who had developed paralysis after administration of OPV. The results enumeratedÂ for the first time the mutations that distinguish the Sabin vaccine from its neurovirulent parent. More importantly, the genome sequence of the vaccine-associatedÂ isolate proved that it was derived from the Sabin vaccine and was not a wild-type poliovirus.
We now understand that every recipient of OPV excretes, within a few days, viruses that are more neurovirulent that the vaccine strains. This evolution occurs because during replication of the OPV strains in the human intestine,Â the viral genome undergoes mutation and recombination that eliminate the attenuating mutations that Sabin so carefully selected by passage in different hosts.
From 1961 to 1989 there were an average of 9 cases (range, 1-25 cases) of vaccine-associated paralytic poliomyelitis (VAPP) in the United States, in vaccine recipients or their contacts, or 1 VAPP case per 2.9 million doses of OPV distributed (illustrated). Given this serious side effect, the use of OPV was evaluated several times by the Institute of Medicine, the Centers for Disease Control and Prevention, and the Advisory Committee on Immunization Practices. Each time it was decided that the risks associated with the use of OPV justified the cases of VAPP. It was believed that aÂ switch to IPV would lead to outbreaks of poliomyelitis, because: OPV was better than IPV at protecting non-immunized recipients; the need to inject IPV would lead to reduced compliance; andÂ IPV was known to induce less protective mucosal immunity than OPV.
After the WHO began its poliovirus eradication initiative in 1988, the risk of poliovirus importation into the US slowly decreased until it became very difficult to justify routine use ofÂ OPV. In 1996 theÂ Advisory Committee on Immunization Practices decided that the US would transition to IPV and by 2000 IPV had replaced OPV for the routine prevention of poliomyelitis. As a consequence VAPP has been eliminated from the US.
OPV continues to be used in mass immunization campaigns for the WHO poliovirus eradication program, because it is effective at eliminating wild polioviruses, and is easy to administer. A consequence is that neurovirulent vaccine-derived polioviruses (VDPV) areÂ excreted by immunized children. These VDPVs have caused outbreaks of poliomyelitis in areas where immunization coverage has dropped. Because VDPVs constitute a threat to the eradication campaign,Â WHO has recommended aÂ globalÂ transition to IPV. Once OPV use is eliminated, careful environmental surveillance must be continued to ensure that VDPVs are no longer present before immunization ceases, a goal after eradication of poliomyelitis.
As a virologist working on poliovirus neurovirulence, I have followed the vaccine story since I joined the field in 1979. I have never understood why no cases of VAPP were observed in the huge OPV trials carried out in the Soviet Union. Had VAPP been identified in these trials, OPV might not have been licensed in the US. Global use of OPV has led to near global elimination of paralytic poliomyelitis. WouldÂ the exclusiveÂ use of IPV have brought us to the same point, without the unfortunate cases of vaccine-associated paralysis? I’m not sure we will ever know the answer.
Update: As recently as 1997 DA Henderson, architect of smallpox eradication, argued that developed countries should not use IPV, because it ‘implies accepting the potential of substantial penalties while reducing but not eliminating, an already extremely small risk of vaccine-associated paralytic illness’.