The Dawn of Malaria’s Doom

A  chicken clucks through the aisles picking at crumbs on the concrete floor of New Tafo Government Hospital. The waiting area is crowded, so the bird is finding plenty to eat. Dozens of colourfully dressed women wait here for hour after hour, most holding babies. Every few minutes, as vaccinators call the mothers one by one to the doctor, an infant gives an indignant cry as it receives a shot. Not all the mothers know the details of the protection their child is receiving, but they do know the vaccine is said to raise their child’s chances of survival substantially. “He cried a lot, but it’s necessary,” says the 25-year-old mother of a three-month old baby. She’s traveled here from the nearby city Bansu, which lies to the northeast of Ghana’s capital Accra – a two-hour drive along bumpy roads. The West African country’s “expanded immunisation programme”, which includes free-of-charge shots to protect against diseases like diphtheria, polio and tetanus, has been key to bringing down mortality rates among children here. Statistically they fell from 155 deaths in 1990 to 60 per 1,000 births in 2014. But one big child-killer remains rampant: malaria.

Silent killer

According to the World Health Organization, the mosquito-born parasite remains the leading cause of premature death in Ghana and other sub-Saharan countries, despite prevention efforts like those promoting bed nets or insecticides. It’s taken more than 30 years of research and development, but the WHO has now finally started its very first vaccination campaign against the disease in three selected countries: Kenya, Malawi and Ghana.
About 360,000 children are now scheduled to receive the protective shots annually between now and 2022. But although this is a truly historic moment in the fight against the devastating disease, no one expects the Mosquirix vaccine (RTS,S/AS01) to end the malaria epidemic just yet. Other­ vaccination technologies – as well as mosquito eradication protocols that employ modern genome editing tools – are already in the pipeline, however, and experts are hopeful that the array of measures could wipe out malaria once and for all. In Ghana, 19% of all recorded deaths are still caused by ‘Atiridii’, the word in Twi for the severe fever generally caused by the parasites Plasmodium falciparum and Plasmodium vivax.

Children under the age of five in particular are at risk of succumbing to the protozoan infection. UNICEF says that in Ghana alone, 5,607 died from it in 2016. Worldwide, malaria takes about half a million lives every year. 90% of its victims are in sub-Saharan Africa, and about 50% of them are children under five. The scale of those numbers helps explain why the WHO decided to begin a nearly US$50m pilot implementation trial with a vaccine that’s far from perfect. Clinical trials reveal that it lowers infection rates by just 27% in babies between six and twelve weeks of age, and offers only 46% protection at best for infants between five and seventeen months. Considering the lack of other viable options, however, says Kobena Awotwe Wiredu, it’s “better than nothing”. Wiredu is the medical superintendent at New Tafo Government hospital, which is taking part in the WHO’s malaria vaccine pilot programme. Even after decades of work, malaria remains a very tough disease to fight in this part of the world.
That’s largely due to the complexity of the parasite, which has various stages and self-protective mechanisms that the protozoan develops in the mosquito on the one hand and humans on the other, says Peter Kremsner from the Institute for Tropical Medicine at the University of Tübingen, who was involved in the RTS,S/AS01 clinical trials. Until now, no vaccine approach has been able to trigger a 100% protective immune response to the variable pathogen. So despite all its limitations, the partial vaccine is still “a big step, and an important breakthrough in vaccine research,” says the member of the WHO’s Malaria Expert Team. “It’s the first vaccine against a human parasite – ever.”
“What we need are multiple tools for malaria protection,” says Seth Berkley from the Global Vaccine Alliance (GAVI), a public-private partnership involving the Bill and Melinda Gates Foundation, the WHO, UNICEF and the World Bank, “and the vaccine brings another tool.” Together with the Global Fund and Unit­aid, GAVI provided the funding for the implementation pilots in Ghana, Kenya and Malawi.
“The purpose of the implementation trial is to find out if RTS,S is practical for real-world use,” says Berkley. And there is reason enough to doubt whether what was tested in strictly regulated clinical trial settings will prove to have a protective effect in real conditions in sub-Saharan Africa. “Ghana already has a very good immunisation system,” says Berkley, but the malaria vaccine shots need to be given outside normal immunisation schedules – long after mothers bring children to local hospitals for routine vaccinations. “The challenge here,” he notes, “is that you have to teach the parents to come at times when they normally wouldn’t come.” Whereas routine shots are mostly finished by the time the infant is three months old, the malaria vaccine needs to be given at around five, six and seven months, then boosted at approximately 15-18 months. “The WHO malaria expert group and the immunisation group both decided that we need to understand whether mothers will bring their children, and what the effects will be,” says Berkley. That means a universal recommendation for the vaccine remains uncertain.

Social challenges

Anthony Asare is confident the programme could work, and believes the WHO will finally decide to organise global access to the vaccine. “The last vaccination dose will be the difficult one,” says the Director General of Ghana’s Health Service. “But with social mobilisation and education, I think the mothers will come.” A big part of the project will involve education. “We are going to community leaders, to churches and mosques, to Face­book, Whatsapp, Instagram, Twitter, etc.” He doesn’t believe people will stop using mosquito nets or spraying insecticides just because they’ve received a malaria vaccine. “We’re not going to stop the other methods, and we’re hopeful that by adding the vaccine, we can bring down the burden very fast.”
People in sub-Saharan Africa still don’t have many other options than to remain optimistic. Berkley says it will take a few years before better vaccines are available:  “The WHO estimates that it will take at least a decade before the next vaccine is available.” That’s why Kremsner recommends the use of RTS,S, although scientists might have developed next-gen malaria vaccine candidates that are even more effective. The Tübingen researcher says his institute’s vaccine is the next most advanced of those in the pipeline. His team decided to use living malaria sporozoites in trials. Before application, they have to be collected from the insects and attenuated by radiation. “We’re almost done with Phase II studies,” Kremsner says, ”and already have a vaccination scheme ready for a pivotal Phase III study.”

Ongoing follow-up studies

A second sporozoite-based vaccine that uses the malaria drug chloroquin to control the parasites is in an earlier stage, but is showing promising results. In a recently published study, it claimed to have provided 100% protection to 67 healthy volunteers (Nature, 542: 445-449).
At the Centre de Recherches Médicales de Lambaréné (CERMEL) in the city of Lambaréné in Gabon, Krems­ner is conducting another Phase II study to determine whether his trial results are robust in an African setting. “We’ll know in autumn of this year,” he says. If promising, approval studies could then start in Europe and the US, followed a little later by ones in Africa.
Although applauded, Kremsner’s approach faces challenges. “The bottleneck is the manufacturing process,” says Trevor Mundel, the President of Global Health at the Bill and Melinda Gates Foundation. “You’d need hundreds of thousands of people dissecting those parasites out of mosquitos.” A valid point, although Sanaria – the US-based company Krems­ner works with – has announced they have solved the problem. “Essentially, they found a way to get the parasites out of the mosquitos, to freeze, store and thaw them to prepare the vaccine,” Kremsner says. He claims that using “sophisticated methods”, it’s now possible to circumvent the mosquito as a sporozoite source: “We now have a system that no longer relies on higher organisms.” Mundel, how­ever, remains unconvinced: “I don’t think this has been demonstrated, at least not at scale.” But even if sporozoite production problems are solved, another pressing issue remains. “The vaccine needs to be given intra­venously,” he says, “which is un­usual for vaccines.” Although it’s known that this administration route improves efficacy dramatically in some vaccines – raising the standard tuberculosis vaccine BCG from 30% effectiveness to 100%, for instance – Mundel says providing intravenous vaccines in a global health setting “is a tough challenge.”
Instead, he’s chosen to invest his foundation’s funds in antigen-based vaccine approaches: “The one fantastic thing that the RTS,S vaccine shows us is that a vaccine against malaria is possible.” According to Mundel, the main problem is that scientists still have no clue why the vaccine’s initial relatively high protective efficacy drops so significantly over time. The malaria parasite apparently has many mechanisms that allow it to avoid the immune system, and enable it to replicate better in humans after setbacks. “But at least thanks to RTS,S, we know that the CSP antigen is a good choice,” says Mundel. “So the question is – can we make a second-generation, more effective CSP vaccine?” Some parts of the CSP protein that had a negative influence in the RTS,S vaccine have already been removed, and that should improve its protective effect. In the search for new antigens – although not a believer in Kremsner’s vaccines based on living parasites – Mundel is drawn to research surrounding sporozoites. “That’s because when you give them to volunteers, you see a very strong immune response. And we now have much better tools for finding the antibodies that are produced in that immune response.” Discovering new antibodies means finding new antigens that might be even better. “We already have a couple of interesting candidates,” Mundel says.
“For the last 50 years, we thought we could be smarter than nature and come up with a vaccine using antigens like this,” says Kremsner. A huge range of combinations have been tested, from single antigens to combinations that include viral components from diseases like Hepatitis B – which are included in RTS,S. “More than 30 have indeed shown 100% efficacy,” says Kremsner. “But unfortunately just in mice, not humans.” RTS,S is so far the only exception. “The lesson I’ve learned from the history of vaccination is that working with living, attenuated pathogens is much more promising,” says Krems­ner. That approach has brought very potent vaccines for diseases like cholera, thyphoid, measles, yellow fever and polio. “We went back a hundred years and used the old-fashioned way to make vaccines,” he adds, “and it appears we’ve been quite successful.” Are there other options? According to Krems­ner: “Nothing promising.”
Although Peter Kremsner and Trevor Mundel differ in their approaches to tackling malaria, both would agree that it’s one of the worlds most pressing health problems. “Ultimately, any progress in eradicating malaria would make a big difference, particularly in sub-Saharan Africa,” Mundel says. “People desperately want a solution.” But even discovering the perfect vaccine would be just a start. Delivery in the fledgling health infrastructures of the countries most strongly affected is still a major issue. “We have difficulties delivering even the basic standard infant vaccines – with many countries having vaccine coverage under 30%,” stresses Mundel. “To distribute a malaria vaccine, we need to have an extensive delivery system, because malaria­-stricken areas are often the most remote, most rural areas in countries.” So developing effective vaccines is just one part of the puzzle when it comes to treating this often deadly disease. The other is to make sure the people who need it most will also receive it.