During the 1940’s and early 1950’s polio was the disease dreaded by parents like Meningitis is today. Healthy children were being struck down, paralysed and confined to “iron lungs” either temporarily or for longer periods as a result of something as simple as going to the swimming pool. In the USA a campaign to eliminate paralytic polio was championed by President Roosevelt (himself a sufferer) and driven by charitable donations “The March of Dimes”. It resulted in the development of 2 vaccines during the mid 1950’s, that were hailed as medical breakthroughs and turned the tide against this disease.
Sixty years later, the intense use of these polio vaccines worldwide has placed us on the verge of the global eradication of this virus in a similar manner to the way that smallpox virus was eliminated in the 1970’s. However, unlike smallpox vaccines, it is becoming clear that the polio vaccines which have been instrumental in controlling disease may prevent us from achieving the goal. In these final steps of eradication, NIBSC is playing a number of key roles.
The global workhorse in polio eradication has been the live, but weakened, “Sabin” vaccine. After this virus is given either on a sugar lump or by squirting the salty vaccine into the mouth, it is able to infect cells in the gut and generate immunity. Most important, the vaccine cannot invade the central nervous system and cause the hallmark paralysis of virulent virus. However, work at NIBSC performed 30 years ago uncovered a dark secret of this “harmless” vaccine. By looking at the genetic sequence of virus excreted into the nappies of babies after vaccination, the team was able to show that within a couple of weeks the weakened vaccine reverts to a form able to cause disease again. This risk is not just a theoretical conjecture. In virtually every part of the world apart from Pakistan and Afghanistan, the outbreaks of paralytic polio that are reported arise from infection of unvaccinated susceptible individuals with these reverted Vaccine Derived Polio Viruses (VDPV). Although this weakened vaccine is cheap to produce and safe and easy to deliver because it does not need syringes and needles, the ability to revert is an “Achilles Heel” in the eradication programme. The impact of this observation has been to shape the subsequent global programme of polio eradication.
The alternative polio vaccine that is increasingly used particularly in Europe and North America is the inactivated “Salk” vaccine. This requires growing up vast tanks of virus and then inactivating it with chemicals to produce the vaccine. Although this vaccine requires a syringe and needle to inject it, because the virus is dead it cannot revert which looks like an advantage. However, the biggest challenge for the future is how we produce huge vats of virulent virus in a world that has otherwise eradicated the virus. This would be a huge risk, especially if the virus destined for the vaccine “escaped” and got into the drains, where it could survive for a considerable time. The team at NIBSC are working on the solutions.
NIBSC is a WHO Collaborating Centre (CC) for Reference and Research on Poliomyelitis. One of its jobs in this role is to send expert scientists to vaccine manufacturers around the world at the request of WHO. At the moment, there are an increasing number of companies wishing to produce inactivated polio vaccine to meet the increased demand for this “safer” existing vaccine. Ensuring that these new manufacturers learn from expert advisors ensures that high quality vaccine is produced by these newcomers. Furthermore, many of the new as well as established vaccine producers are considering whether they can produce an effective and safer inactivated vaccine from growing up the weakened “Sabin” strains and inactivating it. There is concern that for some reason inactivated “Sabin” vaccine is not as effective in stimulating the specific anti-polio antibodies (against the D antigen) that protects against paralytic polio. As a result, the work by NIBSC to produce physical standards that are used as references in measuring the D antigen content of these vaccines and the specific antibodies in the serum of vaccinated individuals is critical to establish the effectiveness of these inactivated “Sabin” vaccines.
Within the terms of reference as a WHO CC for polio, NIBSC is one of the seven WHO Global Specialised Polio Laboratories with a role to advise scientists in the network of regional and national diagnostic laboratories that investigate every case of acute flaccid paralysis and determine whether polio infection is involved. They also undertake routine surveillance of sewage for evidence of poliovirus as several other countries do. Israel has a high level of polio vaccination with the inactivated “Salk” vaccine and no recorded cases of polio disease for many years. Worryingly, wild-type polio was detected in sewage samples during 2013-2014. So how can disease causing polio get into the sewers? It had been shown that this virus was imported from Pakistan, one of the two remaining countries endemic for polio. Working with colleagues in Israel, the Institute analysed the properties of virus isolates from samples taken from sewers in that country and established how current vaccines protect against them. It appears that whilst high levels of vaccination can prevent cases of wild-type polio occurring, the absence of disease does not extrapolate to an absence of virulent virus circulating in a population immunised with inactivated vaccine. This information from NIBSC has informed vaccine policymakers who decided to re-introduce the Sabin vaccine in Israel. Certainly, it provides a warning that we must be extremely cautious about stopping polio vaccination, even in countries where there have been no cases of disease for many years!
The NIBSC team has also highlighted another major concern that will shape the end strategy of the global polio eradication. As part of a study in 1995 of gastro-intestinal infections amongst hypo-gammaglobulinaemic patients who have an inherited disease (common variable immunodeficiency) that results in them producing only poor antibody responses following infection, one particular patient was identified that was excreting culturable poliovirus. It transpires that the patient was not diagnosed at birth and so was given the live weakened “Sabin” vaccine. Since 1995, virus has been detected by the NIBSC team in every stool sample collected and the evolution of the virus over more than 20 years has been defined. The virus is fully capable of causing disease. These data once again indicate that vaccination against poliovirus could be necessary for many decades. It will also be advisable to maintain surveillance activities and develop anti-viral therapies to cure these patients.
So how can we get out of this complex web of continuous vaccination? The development of weakened strains of poliovirus that are unable to revert to virulent forms would be one step which would make dealing with situations like the one in Israel described above less hazardous – the vaccine could not itself cause disease if it spread to unvaccinated areas. It would also be better if an inactivated vaccine could be developed using viruses disabled in ways that would prevent them from “escaping” from vaccine plants. Another improvement would be to create synthetic vaccines that do not carry the viral nucleic acid meaning they cannot infect people. All of these approaches are being investigated by the team at NIBSC. A weakened “Sabin-like” vaccine has been designed which appears unable regain virulence like the current Sabin vaccine and this will be tested in people within a year. Producing large amounts of poliovirus in order to prepare the inactivated “Salk” vaccine would be much safer if the virus could only grow in tissue culture and not in people. This is what a specially engineered strain called S19 is able to do. Careful molecular modification of part of the virus nucleic acid has locked in attenuating mutations which do just that. This novel vaccine virus has been taken up by a major vaccine manufacturer to investigate whether it can be scaled up successfully. In an attempt to make an even safer poliovirus vaccine the different proteins that make up the virus coat are being produced in cells in tissue culture in a way that enables them to spontaneously fold up together to make a virus particle, devoid of nucleic acid. The nature of these viral proteins makes this relatively straightforward. However, for native virus, unless viral nucleic acid is inside stabilising the structure then these particles fall apart at just over 30°C. Working with teams at the Universities of Reading, Oxford and Leeds, ways to engineer more stable “empty” virus particles have been devised and the antibody responses generated by this 2nd generation “safe” vaccine are being investigated.
At NIBSC, the knowledge and expertise gained by studying existing vaccines has been translated into these innovative safer new vaccines. Hopefully, the Salk and Sabin vaccines will no longer be needed and, within a generation, polio will be gone forever.