GlaxoSmithKline's anti-malaria RTS,S vaccine, known as Mosquirix, has been given the green light from the World Health Organisation for widespread use. It is not only the first authorised malaria vaccine, it’s also the first vaccine ever recommended for use by WHO to combat a parasitic disease in humans.
There are hurdles ahead though: the four-dose regimen raises logistical challenges, while questions remain over who will pay for it.
Additionally, this new bazooka against malaria is not the easiest weapon to deploy: it hits its target only 30% to 40% of the time.
NPR reports that the recommendation for approval comes after RTS,S showed positive results in a pilot programme in Africa. The vaccine cut malaria cases by 40% and reduced hospitalisations of the potentially deadly disease by nearly a third.
Tedros Adhanom Ghebreyesus, WHO's director general, called the approval of RTS,S a historic moment. “The long-awaited malaria vaccine for children is a breakthrough for science, child health and malaria control,” he said.
The vaccine is given in four doses and the complexity of delivering a four-dose regimen in low-resource settings had raised concerns about how useful the vaccine could be in the real world, reports STAT. For that reason, the WHO’s vaccine advisers previously recommended the vaccine be used first in a pilot programme that began in 2019 in Ghana, Kenya, and Malawi.
All three countries gave the first three shots of the vaccine at monthly intervals starting at either five or six months of age, with the last given 18 months or so after the first — around a child’s second birthday. While the initial doses are given at the time other vaccines are administered, the last is not. It was feared that in remote and rural settings, parents might not bring their children back in for a final dose of the vaccine, limiting the vaccine’s usefulness.
STAT News added that another fear was that parents might assume the vaccine, which only offers partial protection, was more potent than it actually is and as a result, might let down their guard on other malaria prevention measures, such as having children sleep under a treated mosquito net.
But Tedros said the pilot programme had confirmed the vaccine can be effectively delivered through child health clinics and that community demand for the vaccine is strong. More than 800,000 children have already received the vaccine
RTS,S had won regulatory approval for the vaccine from the European Medicines Agency back in 2015 but WHO wanted to wait for the results of this latest pilot programme before recommending it for use in countries with moderate to high levels of malaria transmission. The expectation is that it will be used primarily in sub-Saharan Africa, where the mosquito-borne disease is one of the top killers of children, claiming nearly a quarter of a million lives each year.
Tedros said the approval of the drug was a landmark moment in the fight against malaria, for which no other vaccines exist. The disease killed roughly 400,000 people in 2019, the most recent year for which statistics are available, mostly in sub-Saharan Africa. The biggest toll is on children; an estimated 279,000 children under the age of five died from malaria in 2019.
“As some of you may know, I started my career as a malaria researcher, and I longed for the day that we would have an effective vaccine against this ancient and terrible disease,” Tedros said at the news conference from Geneva last Wednesday. “Today is that historic day.”
The pilot programmes had laid to rest some safety concerns about the vaccine that had arisen during the clinical trials for RTS,S, Kate O’Brien, director of WHO’s department of immunisation, vaccines, and biological told STAT.
Those studies raised questions about whether increased rates of meningitis, cerebral malaria, and an overall increase in deaths among girls were seen in children who had received the vaccines. The trials did not conclude that these concerns were real — the trial investigators felt the signals were due to chance, not causation. But having given the vaccine to more than 800,000 children, it is now clear there is no link, O’Brien said.
Matshidiso Moeti, WHO regional director for Africa, said she’s delighted by the new recommendation.
“For centuries, malaria has stalked sub-Saharan Africa, causing immense personal suffering. The recommendation offers a glimmer of hope for the continent,” she said.
But the vaccine won't be rolling out across Africa tomorrow. It's still unclear where the money to purchase doses will come from. Also it's a complicated vaccination to administer, requiring four injections spread out over the first two years of a child’s life. And given that it only prevents malaria 30% to 40% of the time, this vaccine is far less effective than health officials had hoped.
Pedro Alonso, head of WHO’s Global Malaria Program, said part of the problem is that malaria is a complicated disease. “This is a parasitic disease,” he pointed out. The parasite life cycle plays out in multiple stages in different parts of the human body and in the mosquito hosts. “This is orders of magnitude more complex in terms of the biology of the causative organism [than a virus].”
Decades of research have gone into developing RTS,S. Alonso said he would would love to see a vaccine that was 95% effective in preventing malaria but the scientific community was still a long way off from developing that. “But what we do have right now is a vaccine that can be deployed, that is accepted, that is safe and that can have a massive impact in terms of lives saved and episodes of malaria averted.”
Countries that decide to move forward with administering RTS,S still need to figure out how to pay for it and how to integrate it into their childhood immunisation schedules.
GlaxoSmithKline had donated 10 million doses of the vaccine for pilot programmes and has now pledged to deliver 15 million doses a year at a price of 5% above cost. Eventually, GSK says, it plans to transfer production to a producer in India.
Alonso said it would be up to member countries to carry out implementation of the rollout. And funding would need to be raised to help them do so.
While the vaccine does not offer full protection against malaria — and indeed is not as effective as vaccines against many childhood diseases such as measles or rubella — even partial protection can have a big impact on the burden of malaria. WHO experts noted that children who live in countries where the parasite circulates can contract it multiple times a year.
Being repeatedly sick stunts children’s development, said Alejandro Cravioto, chairman of WHO’s Strategic Advisory Group of Experts on Immunization. The SAGE, as it is known, was one of the expert groups advising the WHO on the RTS,S decision.
Dyann Wirth, who chairs WHO’s Malaria Policy Advisory Group, said the world needs more and better malaria vaccines. But Wirth, an immunologist at Harvard’s T.H. Chan School of Public Health, said the decision to proceed with broad use of RTS,S could help spur development of next-generation vaccines.
Development of the vaccine took 30 years of work involving GSK and a network of African research centres with support from the Seattle-based non-governmental global health agency PATH, as well as funding for late-stage development of the vaccine from the Bill and Melinda Gates Foundation.
“It has been a long road, and is extremely exciting to finally be able to say that RTS,S could soon be available – alongside other malaria interventions – to more children across Africa,” Ashley Birkett, head of malaria vaccine development for PATH, told STAT.
The approval of RTS,S comes not a moment too soon, because to make matters worse, it looks as if a new strain of the primary parasite responsible for malaria, Plasmodium falciparum, is sneaky enough to avoid a common way it is detected.
Research led by Ethiopian Public Health Institute’s immunologist Sindew Feleke has shown nearly 10% of malaria cases are missed across Ethiopia’s borders as a result of at least one of the mutations helping the parasite evade rapid diagnostic testing (RDT).
What’s more, an ability to hide from test kits could easily give this mutated strain enough of an advantage to spread, according to the study published in Nature Microbiology.
“False-negative results were common in multiple sites and will lead to misdiagnosis and malaria deaths without intervention,” said University of North Carolina's infectious disease researcher Jonathan Parr. “This is a serious problem for malaria control efforts and a reminder that pathogens are very capable of adapting to survive.”
P. falciparum is the most common and deadliest of parasites responsible for malaria in humans. The parasite infests human red blood cells to clone itself within, and these blood cells eventually burst, sending floods of parasites into the bloodstream, causing waves of fevers and other nasty symptoms. Much of the disease’s management revolves around reducing human contact with the blood-sucking insects.
Rapid diagnostic testing for malaria has helped Ethiopia – Africa’s second-most populous country – make great strides against the disease in the past decade. With around 345 million sold annually, the most common rapid test detects antigens the parasite releases into the bloodstream. This is primarily histidine-rich protein 2 (HRP2), but the test can also be triggered by the closely related HRP3.
But some P. falciparum have mutations where the genetic instructions coding for the proteins (pfhrp2 and pfhrp23) have been deleted.
Studying the blood samples of more than 12,500 patients along Ethiopia borders with Eritrea and Sudan, Feleke and team discovered these genetic variants had caused false-negative results for just under 10% of tests. This is double WHO’s minimum criteria for triggering a change in national diagnostic strategy.
“We also found signs that RDT-based testing and treatment are driving a recent rise in pfhrp2 deletion mutation prevalence, allowing parasites to escape detection,” he said. While the mutations themselves were entirely random, this inadvertent selective treatment is allowing the parasites with either deletion in both the genes or sometimes just one gene or the other to flourish and spread.
The researchers mapped the sequences around the deletions for evidence of evolutionary pressure which revealed that pfhrp2 probably rapidly spread from a single, recent point of origin, with 30 of 31 strains forming a related cluster.
But pfhrp3 has been around longer, present in samples from 2013, and there are a number of different deletion patterns, suggesting it had multiple origins.
Unfortunately, other testing options are not as straightforward, and RDT that works by detecting other molecules produced by the parasite have not performed as well.
The team notes the way they picked up deletions in their study means they would have missed those who are asymptomatic, and they only sampled three sites, so they have not captured a complete picture of what these strains of malaria are doing yet. But evidence from Sudan, Djibouti, and Somalia suggest that the Horn of Africa may already be heavily infiltrated by the mutant P. falciparum.
“New tools are needed to support surveillance of [gene] deletions, determine their true prevalence and understand the forces impacting their evolution and spread,” the team wrote in their paper.
The deletions are also present in South America, where RDT is not common. So they could be conferring some other evolutionary advantage, too, Feleke and colleagues suspect. It's possible that pfhrp2 does too. There is some evidence that pfhrp2 is involved in inflammation seen in severe malaria.
“People infected by pfhrp2/3-deleted parasites may have less severe disease and therefore be less likely to seek treatment, increasing the likelihood of onward transmission,” the researchers said. But they can’t yet rule out the possibility that its surrounding genes, also impacted by the deletion, are what’s driving the parasite to become fitter. One of the flanking genes called EBL-1 is involved in P. falciparum’s invasion of red blood cells.
“Surveillance across the Horn of Africa and alternative malaria diagnostic approaches in affected regions are urgently needed,” said Parr.
The ammunition provided by the RTS,S vaccine will go some way towards mitigating the effects of this deadly and determined parasite.
“The vaccine opens up a whole new avenue for malaria control,” said David Schellenberg of WHO’s Global Malaria Program, “and gives health officials a new powerful tool to fight the disease.
“Combined with bed nets, spraying for mosquitoes and new drugs, it could have a major impact in places where malaria remains a chronic problem,” he added.
Study details
Plasmodium falciparum is evolving to escape malaria rapid diagnostic tests in Ethiopia
Sindew M. Feleke, Emily N. Reichert, Hussein Mohammed, Bokretsion G. Brhane, Kalkidan Mekete, Hassen Mamo, Beyene Petros, Hiwot Solomon, Ebba Abate, Chris Hennelly, Madeline Denton, Corinna Keeler, Nicholas J. Hathaway, Jonathan J. Juliano, Jeffrey A. Bailey, Eric Rogier, Jane Cunningham, Ozkan Aydemir & Jonathan B. Parr
Published in Nature Microbiology 27 September 2021
Abstract
In Africa, most rapid diagnostic tests (RDTs) for falciparum malaria recognize histidine-rich protein 2 antigen. Plasmodium falciparum parasites lacking histidine-rich protein 2 (pfhrp2) and 3 (pfhrp3) genes escape detection by these RDTs, but it is not known whether these deletions confer sufficient selective advantage to drive rapid population expansion. By studying blood samples from a cohort of 12,572 participants enroled in a prospective, cross-sectional survey along Ethiopia’s borders with Eritrea, Sudan and South Sudan using RDTs, PCR, an ultrasensitive bead-based immunoassay for antigen detection and next-generation sequencing, we estimate that histidine-rich protein 2-based RDTs would miss 9.7% (95% confidence interval 8.5–11.1) of P. falciparum malaria cases owing to pfhrp2 deletion.
We applied a molecular inversion probe-targeted deep sequencing approach to identify distinct subtelomeric deletion patterns and well-established pfhrp3 deletions and to uncover recent expansion of a singular pfhrp2 deletion in all regions sampled.
We propose a model in which pfhrp3 deletions have arisen independently multiple times, followed by strong positive selection for pfhrp2 deletion owing to RDT-based test-and-treatment. Existing diagnostic strategies need to be urgently reconsidered in Ethiopia, and improved surveillance for pfhrp2 deletion is needed throughout the Horn of Africa.
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