GlaxoSmithKline PLC will seek marketing approval for the world's first malaria vaccine next year with a view to rolling it out in Africa from 2015, after trial data showed the treatment reduced the number of cases of the disease in African children.

GSK’s RTS,S malaria vaccine cut infections by 46% in infants aged 5-17 months when they received the initial dosage, and by 27% for 6-to-12-week-old babies, over an 18-month period in a Phase III trial that involved over 15,000 children in Africa.

The three-shot regime also reduced severe malaria by 36% and hospitalizations by 42% among older infants, although reductions for the entire cohort of all patients did not reach significance. The results weren't as strong as those from earlier data, while the effectiveness of the vaccine falls over time.

Still, the fact RTS,S continued to protect young children and infants from clinical malaria up to 18 months after vaccination has persuaded GSK to submit it to the European Medicines Agency in 2014 for authorization with a view to making it available in late 2015. If the drug makes it to market, it would be the world's first vaccine for malaria, which kills 660,000 people a year, 90% of them African children under the age of five.

The latest readout from the malaria trial was presented on Oct. 8 at a medical meeting in Durban, South Africa.

Long Ongoing Process

Scientists have long been working to find a viable malaria vaccine; a difficult task given the disease is caused by five different species of parasites. No effective vaccine has ever been developed against a parasite, although many candidates are currently under development around the world.

The Phase III efficacy trial of RTS,S started in May 2009 and is still underway at 11 sites in seven African countries: Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and Tanzania, with 15,460 infants and young children participating, making this the largest malaria vaccine trial in Africa to date. It is scheduled to continue generating data until 2014 and is being paid for by GSK and the PATH Malaria Vaccine Initiative.

Hopes that RTS,S would be the answer were hurt in November 2012 when results from a final-stage trial with 6,537 babies aged six to 12 weeks showed that those who got three doses of the vaccine had about 30% fewer cases of malaria than those who didn't get immunized ([A#28121112007]). The sponsors had been hoping for a higher response rate.

GSK’s vaccine is the product of nearly three decades of trial and error R&D ([A#00130930006]). Britain’s biggest drug maker first developed the vaccine in 1987 and has invested more than $350 million in it so far and expects to invest more than $260 million until development is completed. It brings together Crucell NV’s Ad35CS and GSK’s RTS,S/AS, both recombinant proteins [See Deal].

It also contains Agenus Inc.’s QS-21 Stimulon adjuvant, a saponin extracted from the bark of the Quillaja saponaria tree, an evergreen tree native to warm temperate central Chile. Agenus, which changed its name from Antigenics in 2011, has been a longtime partner of GSK Also see "Agenus Extends Cash Runway In GSK Partnership Expansion" - Pink Sheet, 5 March, 2012..

There are currently 21 development programs underway involving vaccines using QS-21 Stimulon for treating various forms of cancer, infectious diseases and degenerative disorders - including RTS,S for malaria, MAGE-A3 cancer immunotherapeutic for non-small cell lung cancer and melanoma and HZ/su for shingles. In addition, Janssen’s QS-21 Stimulon adjuvant-containing vaccine candidate is in Phase 2 trials for the treatment of Alzheimer’s disease, and Agenus’ HerpV, a therapeutic vaccine for the treatment of genital herpes, is in a Phase 2 trial.

RTS,S uses cutting-edge platform technology, the cost of which has been spread across many other projects, including its approved pandemic influenza vaccine and its developmental efforts in therapeutic cancer vaccines.

GSK has meanwhile promised that if RTS,S is given the market go-ahead, it will be priced at cost of manufacture plus a 5%, and the margin would be reinvested in malaria research.

GSK’s CEO Andrew Witty is very keen to find treatments against malaria. In 2010 he gave scientists and researchers access to his company’s library of 13,500 compounds that have shown some activity against the disease Also see "GlaxoSmithKline Offering Free Access to Potential Malaria Compounds" - Pink Sheet, 25 January, 2010..

Explaining his enthusiasm for RTS,S, Witty said in a statement, “While we have seen some decline in vaccine efficacy over time, the sheer number of children affected by malaria means that the number of cases of the disease the vaccine can help prevent is impressive. These data support our decision to submit a regulatory application for the vaccine candidate.”

Variation In Response

In 2006, a group of experts led by the WHO said a malaria vaccine should cut the risk of severe disease and death by at least half and should last longer than one year.

Allan Pamba, a physician who joined Glaxo in 2005 and was involved in leading R&D programs in Africa, said further study was needed to better understand why RTS,S may be working differently in different regions there. One unknown is whether babies born in areas with high levels of malaria might inherit some antibodies from their mothers, which could interfere with any vaccination.

“We have a number of theories why the very young – the 6-to-12-week-old babies – had a less positive response. For example, it could be that their immune system is still not fully developed,” he said in an interview.

Another possibility is that the youngest age group had the RTS,S vaccine co-administered with medicines against DPG (brain tumor diffuse pontine glioma), Hepatitis B and polio, whereas the older group had only received the GSK malaria vaccine.

Filing Rationale

Pamba said GSK will not be filing the malaria vaccine in the US or Europe, as it is designed only to be used in children in sub-Saharan Africa who are most at risk of malaria.

“We are filing it with the EMA because this vaccine is specifically developed for African children given that 90% of the 660,000 who die of malaria every year are African children below the age of 5. Because African countries don’t have regulatory bodies who can review data like this – there are one million pages connected with RTS,S – the European Medicines Agency just happens to the western regulatory body that it falls to.”

Many African authorities rely on regulatory approval from EMA for vaccines which is why GSK is following this process.

For others, there would be an additional step. The United Nations health agency, the Geneva-based World Health Organization (WHO), has indicated it may recommend use of the RTS,S vaccine from as early as 2015 if EMA drugs regulators back its license application. That would pave the way for decisions by African nations regarding large-scale implementation of the vaccine through their national immunization programs for use alongside other malaria control measures, such as bed nets and anti-malarial medicines.

“If it is recommended by EMA, it will then be considered by WHO, and if WHO grants pre-qualification, it could then be licensed in individual countries in Africa,” Pamba said. But even where a WHO review is required, the vaccine will be available in late 2015 if all goes according to plan.

GSK Prepares For Malaria Vaccine Roll-Out In Africa By 2015

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