LONDON – More than 30 years after its initial discovery, the first malaria vaccine – and also the first to be active against a human parasite – is about to be tested as part of routine childhood immunization, in a pilot program in Ghana, Kenya and Malawi.

The pilot aims to vaccinate a total 360,000 children per year, to evaluate the feasibility of delivering the four required doses of Glaxosmithkline plc's Mosquirix (RTS,S) and assess the vaccine's effectiveness in a real-world setting.

"This landmark is a long-awaited step in the fight against malaria," said Kate O'Brien, director of the department of immunization at the World Health Organization (WHO). "This is the first and only vaccine to show some protection against malaria in children and the first to reach children in Africa through routine immunization, not a clinical trial," she said.

It has taken almost four years from when the EMA approved Mosquirix in July 2015 to the first child being vaccinated in Malawi on Tuesday as part of routine health care.

EMA approval was granted on the basis of a phase III program, conducted between 2009 –2014 and involving 16,000 children in 13 African research centers, in eight countries.

That showed dosing at 5, 6 and 7 months of age, followed by a booster at 15 to 22 months of age, reduced cases of malaria by 39% over three years of follow-up.

The vaccine prevented 29% of cases of severe malaria and reduced the number of hospital admissions and the need for blood transfusions to treat severe anemia that can occur when the parasite is released from the liver to the bloodstream, and invades and ruptures erythrocytes.

"It is an imperfect vaccine against a very complex disease, but it has the potential to save lives," said O'Brien. Vaccines are important in being able reach and protect people in places where there is no treatment once they contract the disease, and can offer one of the best returns on investment of any intervention, O'Brien said.

Speaking from Malawi, where she had just seen the first children being vaccinated with Mosquirix, Mary Hamel, WHO's senior technical officer in the implementation program, agreed. "It is not a perfect vaccine, but in an area where children suffer six or more episodes of malaria a year, it has public health potential," Hamel told attendees of the teleconference held to discuss the first use of the product outside a clinical trial.

The implementation program for Mosquirix is being coordinated by WHO in collaboration with the national ministries of health of the three countries and funding from the nonprofit bodies, including the GAVI vaccine alliance; the Global fund to fight AIDS, tuberculosis and malaria; and Unitaid.

The data on how Mosquirix performs in the pilot will inform WHO's decision-making on recommending wider use. While the pilot will last for four years, Hamel said there will be enough evidence for WHO to complete its evaluation in two years.

In addition to assessing adherence to dosing, how the schedule fits with existing childhood immunization programs and examining the motivations of families choosing to have children vaccinated with Mosquirix – or not – the evaluation will study cost effectiveness.

GSK conducted early research on Mosquirix in collaboration with the Walter Reed Army Institute for Research before forming a public-private partnership with the nonprofit organization PATH in 2001. The company invested $365 million to get to the point of EMA approval, with PATH contributing $200 million.

In April 2015, GSK estimated it would cost it a further $200 million to $250 million to complete the Mosquirix program. The company is donating up to 10 million doses for use in the implementation program and will be conducting phase IV studies in parts of the pilot areas. Those will gather additional data on effectiveness and side effects associated with routine use.

The side-effect profile in phase III was similar to that seen with other vaccines. There were more cases of meningitis in children vaccinated with Mosquirix, and while that was not associated with the vaccine, it will be followed up in phase IV.

If positive feedback from the pilot leads WHO to recommend broader use of Mosquirix, there is an agreement in place among GSK, PATH and WHO to ensure there is a supply of the vaccine. GSK has pledged to sell the product at the cost of manufacturing, plus 5%, and said that profit will be re-invested in vaccines research.

The active ingredient of Mosquirix consists of amino acids found in the circumsporozoite protein that is secreted during the sporozoite stage of the parasite's life cycle, after it enters the bloodstream through a mosquito bite, but before it establishes itself in the liver to mature and multiply. The vaccine, manufactured in recombinant yeast cells, also contains GSK's proprietary adjuvant, AS01.

As malaria control stalls, new measures are needed

Malaria is one of the biggest killers of children worldwide, causing the deaths of more than 200,000 each year. The majority of those cases are in sub-Saharan Africa, and Mosquirix has been specifically developed to protect children under the age of 5 from Plasmodium falciparum, the most virulent and most prevalent mosquito-borne parasite in the region.

WHO's latest report on the global malaria burden, published on Nov. 19, 2018, shows new means of controlling the disease are urgently needed. After great strides in malaria control between 1990 and 2015, progress stalled in 2015 to 2017.

There were 217 million recorded cases in 2016 and that rose to 219 million in 2017, when there were 435,000 deaths.

Around 200 million of the cases in 2017 were in Africa, despite $2.2 billion being spent on control and elimination programs. The 10 countries in Africa with the highest levels of infection all reported more cases in 2017, compared to 2016.

WHO is stressing that Mosquirix is a complementary malaria control tool, to be added to the core package of measures including insecticide-treated bed nets, indoor spraying with insecticides, malaria testing and treatment.

Despite what he termed "modest efficacy," Pedro Alonso, director of the global malaria program at WHO, said Mosquirix "may help in getting us back on track in the aim of eliminating malaria."

There are around 20 other malaria vaccines in development, and Alonso said WHO is "taking a keen interest" in work in progress in labs around the world. But it does not make sense to wait for a more effective second-generation vaccine, he said.

"We know we are dealing with a very hard to beat organism; parasites are much harder than bacteria or viruses, and second-generation products may be many years away," said Alonso. Mosquirix "may have modest efficacy, but it is one we believe can be translated into massive impact."