Anti-malaria vaccine a few tests away

April 25 is World Malaria Day and there are several reasons to celebrate. According to the World Health Organisation, malaria mortality rates in Africa have dropped by a third since 2000.

Another piece of good news is that a malaria vaccine is now within sight. If all goes well, by 2015, the world may have its first malaria vaccine, which will help reduce malaria by half and offer protection for at least a year.

Globally, there are 219 million cases of malaria every year, resulting in 660,000 deaths. Each minute, a child is dying of malaria. A vaccine that offers 50 per cent reduction of these figures will save hundreds of thousands of lives and reduce the cost of patient care, especially in sub-Saharan Africa, where over 80 per cent of malaria cases  and 90 per cent of malaria deaths occur.

This much-awaited candidate goes by the name RTS,S, but the research community is aware that a lot still needs to be done. A vaccine that reduces disease by 50 per cent, with protection lasting for only a year, can be improved.

The World Health Organisation (WHO) produces updates on malaria vaccine candidates, listing those in various stages of development. The December 2012 report indicated that over 45 malaria vaccine candidates were in various stages of development in the laboratory as well as in animal and human testing.

So far, over 30 vaccine candidates have been discontinued, and researchers are working to improve RTS,S in the hope that, by 2025, the world will have a malaria vaccine that reduces the disease by 80 per cent and protects for longer.

A look at the story of RTS,S paints a picture of hard work and perseverance. In a 2009 article in the scientific journal Human Vaccines, Dr Joe Cohen, the co-inventor, outlined his trials and tribulations.

In 1984, Dr Cohen joined SmithKline and French (now GlaxoSmithKline — GSK) in Belgium as a senior scientist. After a few years, he was asked to head GSK’s malaria vaccine programme. At the time, the Walter Reed Army Institute for Research (WRAIR) was keen on developing a vaccine to protect its military forces when stationed in countries where malaria is common.

Doctors Ruth and Victor Nussenzweig had already discovered that the circumsporozoite protein (CSP) of the malaria parasite had the potential of offering protection if used in a vaccine. Dr Cohen combined CSP with a protein from the virus that causes hepatitis B infection — and RTS,S was invented.

With WRAIR, studies were conducted in laboratory animals to look out for toxic effects and determine whether the product could move to studies in human beings.

The initial trials in humans of a new drug or vaccine are called Phase 1 clinical trials or safety trials. As the name suggests, these trials determine the safety of the product in humans. It is also the time to perfect dosages and determine how the product shall be given (oral or injection). For RTS,S, the safety studies were conducted among Belgian and US adult male volunteers. In 1992, the formulation protected two out of eight volunteers from malaria.

But, although it showed some protection, it was not sufficient and scientists started trying out different adjuvants to put into the formulation.

Adjuvants are chemicals added to vaccine formulations to make them stimulate the body’s immune system. They often contain bacteria products that the body’s immune system is quick to sweep up and, in the process, take on the required vaccine components.

The adjuvant that was used for the first RTS,S vaccine was called AS02, and it was found to protect six out of seven adult male US volunteers from acquiring malaria.

Vaccine development had reached a crucial stage. The scientists now had the formulation and dosage right. They knew the product was safe and effective among adult men in America and Belgium, and it now needed to be tested in areas where people suffered from malaria to see whether it was as safe and effective there.

In 1998, about 150 adult male volunteers in The Gambia who received the vaccine were compared to 150 who did not. The candidate vaccine was found to be safe and provided 34 per cent protection.

Although the data suggested that RTS,S was protecting people against malaria, the levels of protection were not high enough for it to be considered for military personnel or travellers. But it was obvious that it would be useful in lowering malaria among the most vulnerable group; African children.

However, GSK is a profit-making pharmaceutical company and investing money in a malaria vaccine which would be marketed in poor countries did not seem like a good income-generating venture. 
The nations with the highest burden of malaria would not be able to afford the price that GSK would need to charge for the vaccine in order to recover the costs of clinical development. Still, the company not averse to continuing the work on the vaccine as long as Dr Cohen and his group would raise money for the trials required.

As luck would have it, Bill and Melinda Gates launched their foundation in 2000. Based on the promising data from The Gambian study, the Bill and Melinda Gates Foundation provided funding through the Programme for Appropriate Technology in Health (PATH)—Malaria Vaccine Initiative (MVI) to develop the vaccine for African children.

The public-private partnership between GSK and PATH—MVI was signed in January 2001, and the upshot if it all was that PATH—MVI would provide funding for clinical development of the vaccine on condition that GSK would make the vaccine available at an affordable price where it was needed.

Safety trials were conducted in The Gambia among children, starting with six to 11-year-olds, then the one to five-year-olds. The trials showed the vaccine to be safe in children using the selected doses.

In 2003, the first Phase II trial in African children was conducted in Manhica district in Mozambique among 2,000 children aged one to four years. Phase II trials determine whether a product has substantial protective effect in order to move into the next stage of development. When the trial was over, Dr Cohen and all the other investigators travelled to Mozambique on the day the trial results were unveiled.

 “We were packed into a small sweltering room fighting to conceal out anxiety. No one spoke while the statisticians crunched numbers. For me it was the moment of truth. A failure at this stage could ring the final bell for this project that had become an integral part of my professional life for the past 17 years,” said Dr Cohen.

But the results, published later in the Lancet of 2004, showed that the vaccine reduced infection with malaria parasite by 45 per cent, meaning that about half of the vaccinated were able to avoid getting malaria parasites in their blood when bitten by mosquitoes, compared to those that did not get the vaccine. The vaccine also protected one in every three vaccinated children from getting clinical malaria.

However, the strongest impact was on severe life-threatening malaria. Eleven out of over 700 children had severe malaria among the vaccinated group compared to 26 out of over 700 in the non-vaccinated group.

“Our anxiety gave way to unbridled relief and exultation,” said Dr Cohen.

At this point, the scientists at GSK had developed a new adjuvant — AS01. This formulation was tested on several US adult volunteers and adult men in Kilifi, Kenya, to confirm its safety and ensure that it did produce a stronger immune response than the previous adjuvant.

The new formulation was tested in a Phase II trial conducted in 447 children aged five to 17 months in Kilifi and Korogwe in Tanzania. The vaccine was found to provide 53 per cent protection against clinical malaria. In eight months of follow-up, those who had received the vaccine experienced 38 episodes of malaria and those that did not receive the vaccine, eight episodes.

Although some protection against severe malaria was observed, children enrolled in the study were too few for the evidence to be conclusive.

Since the vaccine would hopefully be used as part of the Expanded Programme of Immunisations (which include polio, measles, BCG, DPT, Hib etc), it was important to find out if the RTS,S vaccine interfered with these established vaccines or whether these vaccines interfered with the performance of the candidate vaccine.

A study was conducted in Tanzania in which 170 children aged six to 12 weeks were given the RTS,S vaccine while they received the established vaccines. This study, published in 2008, reported that RTS,S  was safe to use in this age group, it did not interfere with the performance of established vaccines, and that it also offered higher protection for this age group compared to older children.

The vaccine was now ready for Phase III trials, which started in March 2009 and has recruited 15,460 children in 11 sites in seven countries across Africa. There are two sets of children, one group is aged five to 17 months and the other six to 12 weeks. These children are still being followed up and the final result will be out by 2014.

There are several basic requirements for a vaccine to be effective, but among the key ones is that it must be safe and offer protection that can be sustained. RTS,S has been proven to be safe since it has so far been used in over 18,000 children without any report of serious side effects.

It has also been proven to have a protective effect, both in infants and older children. The only niggling aspect is that data suggests that the immunity generated from the vaccine does not last long.

The results from the Phase II trials in Kilifi where 447 children were recruited showed that the vaccine was protective against malaria. However, the scientists, led by Dr Ally Olotu, a senior research scientist at the Kemri-Wellcome Trust programme in Kilifi who is also a PhD student at Oxford University, decided to extend the follow-up by an extra three years in order to observe whether this protective effect was sustained.

Although the vaccine showed 45 per cent protection in the first year of follow-up, by the fourth year, there was no difference between those who received the vaccine and those who did not.

‘This underscores the importance of long-term follow-up as this is the only way we can tell if the vaccine has long-term protection. This was, however, a small study where only 320 children had full follow-up.

This is, therefore, not the final word. The results from the Phase III trials that involve more than 15,000 children will be more conclusive. The use of booster vaccination can also deal with this waning immunity,’ said Dr Olotu.

In the trial involving more than 15,000 children, a booster vaccination will be provided to a third of the study participants 18 months from the first dose. This study will therefore show conclusively the length of protection the vaccine will offer and whether a booster vaccination will help prolong the protection.

However, initial data from a year of follow-up of the more than 15,000 children has produced some promising results, as published by Dr Patricia Njuguna, the principal investigator for the Phase III trial.

Dr Njuguna reported that RTS,S was able to reduce malaria episodes in children aged five to 17 months by half and by a third in those aged six to 12 weeks. Bear in mind that these children are also using insecticide-treated bed nets.