Now free Africa of vaccine-derived poliovirus

Even as the World Health Organization (WHO) prepared to declare Africa free of wild poliovirus at the end of August, it knew the fight was far from over.

Earlier that month, Sudan had officially reported a new outbreak of poliomyelitis. Two cases of what's called vaccine-derived poliovirus had been confirmed in the Sudanese states of South Darfur and Gedaref.

Environmental samples of poliovirus type 2 had also been found circulating in seven other states in Sudan. The WHO said those environmental samples indicated a "wide circulation of the virus."

That puts about 5.2 million children at risk of contracting the disease, which in extreme cases can cause paralysis, especially in children under the age of five.  Polio can also be fatal if the virus affects breathing muscles.

Fourteen other African countries have cases of circulating vaccine-derived poliovirus, or cVDPV. None of them have reported cases of wild poliovirus (WPV) in recent years.

"It is a very disappointing setback we're facing with vaccine-derived poliovirus, but that shouldn't undermine the incredible success we've achieved in eradicating wild poliovirus in Africa," says Dr. Michel Zaffran, outgoing director of the WHO's polio eradication program. 

So, what's the difference between WPV and cVDPV?

WPV is a naturally occurring form of poliovirus. While cVDPV is derived, as the name suggests, from an oral polio vaccine, known as the Sabin vaccine, or OPV.

The oral polio vaccine is used to immunize children against the wild forms of poliovirus. It uses live but genetically modified versions of the virus.

These so-called vaccine-viruses need to be active — as close to the real thing as possible — without making the recipient sick. They have to replicate in the child's gut, just as the real virus does, to spark an immune response and have the child's body develop long-term protection.

The problem is that these vaccine-viruses are shed from the body and can survive in communities where sanitation standards are poor.

Then, through a complex process, there is a risk that the vaccine-virus can mutate back into a stronger, virulent form of the virus, circulate in a community, for instance in contaminated drinking water, and infect unvaccinated people.

"The risk is quite significant because there's a large proportion of children who have never been exposed to a type 2, live attenuated vaccine-virus," says Zaffran (attenuated viruses are deliberately weakened or less virulent). 

"As a result, the outbreaks are spreading. We are responding, and we are successful in stopping those outbreaks, but because of the low immunity, a vaccine-derived poliovirus can spread to areas outside of the area where a response is taking place."

Three types, times two

There are three types of wild poliovirus — types 1, 2 and 3 — and, correspondingly, three types of circulating vaccine-derived poliovirus — cVDPV1, 2 and 3.

"Type 2 of wild poliovirus has not been seen since 1999 and type 3 not since 2012," says Zaffran. "Both have been officially declared eradicated."

That leaves just WPV type 1 in circulation, which remains endemic in Pakistan and Afghanistan. "I wouldn't compare the two countries, they are different," says Zaffran, "but Pakistan could eradicate the wild virus, they just need to decide to do so."

As for vaccine-derived poliovirus, the most common types of cVDPV are type 2, and not just in Africa. As recently as 2019, there were cases of cVDPV2 in the Philippines and China, while cVDPV1 was found in Myanmar and Indonesia.

A report published by the US Centers for Disease Control and Prevention in April cited 31 ongoing and new cVDPV2 outbreaks between July 2019 and February 2020. Nine of those outbreaks spread internationally.

"Polio is still circulating in a few areas and that comes from the way that eradication has been done," says Dr. Andrew Macadam, a principal scientist at the UK's National Institute for Biological Standards and Control. "It was carried out using a live attenuated virus. And because it's live (infectious), it replicates and can mutate and evolve over time."

Changing the way eradication is done

Macadam is part of an international consortium that has been working on a novel oral polio vaccine. It's called nOPV2 and it may just be the first major upgrade for global polio vaccination programs in 50 years.

The original oral polio vaccine was developed by Albert Sabin, as a trivalent vaccine. This means it contained each of the three types of poliovirus.

After the eradication of wild type 2 poliovirus, the most "useful" oral polio vaccine was bivalent (containing two strains) says Macadam: "It so happened that type 2 [of the vaccine-virus] interfered with the efficiency of the other two, so by taking it out of the trivalent, giving you a bivalent, it made the other two work better."

There is also a monovalent OPV (containing one strain), which is used to handle live outbreaks of the disease.

But whichever it is, live attenuated oral poliovirus vaccines come with the risk that the vaccine-virus may mutate and start a cVDPV outbreak, even after the wild type of the virus has been eradicated.

"So, in the face of that issue, the answer would seem to be to develop a new oral live attenuated vaccine, which does all the good things which the old one did but has less ability to evolve back into a wild type of virus," Macadam says.

The order of mutation

Clinical trials so far have shown nOPV2 to be more genetically stable than the current oral polio vaccine — that is, the vaccine-viruses it contains are less likely to mutate into a virulent virus.

The team behind nOPV2 has discovered three steps in the virus' mutation, which appear to happen in a particular order.

First, it loses its attenuation. Second, it re-combines with another form of polio or a "cousin," as Macadam puts it, such as another enterovirus, which on its own would mostly only cause mild symptoms. And third, it adapts further to its environment.

"We don't definitely know that they have to happen in that order, but it is tempting to think they do," says Macadam, "in which case if we stop the first step, then the others shouldn't happen."

So, for instance, the team has designed part of the vaccine-virus in such a way that if it does change through mutation, "it can only become more attenuated," says Macadam. They have also targeted the second step in the process to reduce the risk of a vaccine-virus re-combining with another virus and grow in strength or virulence.

"But, clearly, until you try it out in a large population, you can't know for sure that you haven't overlooked something. So, rolling it out to the entire population would be a little bit premature. And secondly, there simply wouldn't be enough vaccine to do that. You would use it where it is most needed, and that's in areas that are experiencing outbreaks of vaccine-derived polioviruses."

The nOPV2 has gone through two phases of clinical trials and may receive a so-called Emergency Use Listing (EUL) before the end of the year to accelerate its use in communities, and they would aim to distribute 100 million doses at first.

"We were we're thinking that Sudan might be a good candidate for using this vaccine. But the outbreak is spreading now and the local authorities don't want to wait until mid-October to respond to the outbreak," says Zaffran.  

Salk vs. Sabin

Many countries have replaced the Sabin vaccine with what's known as the Salk, or inactivated polio vaccine (IPV). It was developed by Jonas Salk and introduced in the 1950s, about ten years before the Sabin vaccine became a standard in the US.

A Salk vaccine uses an inactivated or killed virus and is given by injection, either into a muscle, into the skin or into a layer of fat under the skin.

It's more expensive to produce because it takes more time to grow a vaccine-virus in a lab and then kill it, with a view to making hundreds of millions of doses.

But the big advantage is that the virus cannot pass into the environment, spread, mutate and cause an outbreak of vaccine-derived poliovirus — simply, because it's already dead.

Over the past 15 years, there's been an effort to stop using Sabin altogether. It's been a slow process, with both financial and scientific problems along the way.

First, there aren't enough doses of IPV in production. About 130 million children are born every year, and every one of them needs protection.

"Based on current WHO recommendations, you would have to give each child three doses of IPV, which means you need about 400 million doses in production," says Dr. Suresh Jadhav, executive director at the Serum Institute in India.

In 2012, the Serum Institute bought a Dutch firm called Bilthoven Biologicals, one of only three companies worldwide making an inactivated polio vaccine. The other two were GSK and Sanofi.

"Back then, GSK and Sanofi production only took care of children in the developed world. It was not available for the developing world," says Jadhav.  

The problem was price.

"I wouldn't call it a bias or discrimination [against the developing world] but a difference in the pricing between OPVs and IPVs," says Jadhav. "The oral polio vaccine cost about $0.15 per dose, if UNICEF was buying it. The inactivated vaccine cost about $3 or $3.50 per dose. And on the private market, in Europe or in the United States, the price was at least 10 times more."

Today, Jadhav says the off-market price of IPVs has come down by about a dollar. He says IPVs are used in over 30 countries in Africa, with Bilthoven Biologicals planning to increase production from about 25 million doses to 100 million doses per year.

But vaccination campaigns still lag behind the outbreaks, and the growing number of cases of vaccine-derived poliovirus in Africa.

The WHO says routine vaccination programs should continue even after wild poliovirus has been eradicated and even where there are no cases of vaccine-derived poliovirus because there is still a theoretical risk that it could return.

Certainly, as long as Pakistan and Afghanistan have circulating poliovirus (of whichever type or form), the whole world is at risk of the virus being reintroduced through global travel, for instance.

"That's the WHO's fear," says Jadhav, "and everyone's waiting for the production of IPVs to meet the quantities needed by UN agencies."

So far, we've "failed"

There is one other problem with IPVs, however — the very thing that makes them good also makes them bad.

The fact that they use killed virus-vaccines means they don't replicate in the human host — they stop the virus developing into a full sickness in people who have been vaccinated, but they cannot stop those people from passing the virus to people who haven't been vaccinated.

OPVs, on the other hand, do stop that kind of transmission.

"So, eradication is only possible with the live attenuated vaccine. That's the one that can stop person-to-person transmission," says Zaffran. "The plan has always been to eradicate the wild virus, then stop using the Sabin vaccine, and replace it with the inactivated Salk vaccine."

The WHO started that process globally in 2016 by introducing a dose of the Salk vaccine in all routine immunization programs. But it hasn't gone to plan.

"Unfortunately, this has been a failure. It's been a failure because too many countries have had poor routine immunization coverage," says Zaffran. "That's allowed some of these [vaccine-derived poliovirus] outbreaks to occur. And we've had to respond by reintroducing the Sabin type 2 vaccine, which has also, over time, caused outbreaks."

It's a difficult dance: You can't stop wild poliovirus without Sabin, but Sabin brings the risk of vaccine-derived poliovirus, and the only way to fight that is with Sabin.

If the novel oral vaccine is as stable as the scientists believe at this stage, it may help to prevent new outbreaks.

But people can act as well. Poliovirus is spread via food or water that is contaminated with fecal matter from an infected person. So, if countries did more to improve sanitation standards, it may relieve some of the pressure on vaccines.