Results of RTS,S vaccine trials boost fight against malaria

A breakthrough in the fight against malaria — Africa’s deadliest killer — appears to be close after the trials of a vaccine returned promising results. The trials were conducted in seven African countries including Kenya and Tanzania.

The trials saw one out of every three infants who were given the new RTS,S vaccine, develop immunity to malaria — a disease that kills about 35,000 people in East Africa every year. RTS,S (the world’s first candidate malaria vaccine) reduces malaria by approximately one–third in African infants, according to the initial results of an ongoing large-scale Phase III trial, published in the New England Journal of Medicine.

When compared with immunisation using a control vaccine, infants (aged 6-12 weeks) vaccinated with RTS,S had one-third fewer episodes of both clinical and severe malaria and had similar reactions to the injection.

“Although clinical investigations will be needed before this vaccine is ready for licensure and implementation, these results bring us an important step closer to developing a vaccine that can provide lasting protection to help save millions of lives,” said Patricia Njuguna, the principal investigator at Kilifi Site at the Kenya Medical Research Institute (Kemri) Wellcome Trust Programme.

The vaccine may become available globally by the end of 2014 and if the promising numbers continue, the World Health Organisation (WHO) plans to recommend its use by 2015. “This will pave the way for countries to make a decision about the implementation of the vaccine through their national infant immunisation programmes,” said Dr Njuguna.

RTS,S is currently the only malaria vaccine under investigation on a large-scale phase III trial in Africa, making it the first malaria vaccine candidate to advance this far.

The study results for the Phase III trial being conducted in 11 centres in the seven African countries also show that the vaccine can be administered safely with other childhood vaccines. “This study indicates that RTS,S can help protect babies against malaria. More importantly, we observed that it provided this protection in addition to the widespread use of bed nets by the trial participants. In this trial, RTS,S demonstrated an acceptable safety and tolerability profile,” said Dr Njuguna.

“We’ve made significant progress in recent years in our battle against malaria, but an effective vaccine would be a welcome addition to our tool kit, and we’ve been working toward this goal with this RTS,S trial. The efficacy is lower than what we saw last year with the older 5-17 month age category. This makes us even more eager to gather and analyse more data from the trials to determine what factors might influence efficacy against malaria and to better understand the potential of RTS,S in our battle against this devastating disease,” said Salim Abdulla, a principal investigator for the trial from the Ifakara Health Institute in Tanzania.

The efficacy of RTS,S observed last year in children aged 5-17 months of age against clinical malaria was 56 per cent, while that of severe malaria was 47 per cent. “This takes us even further on the journey towards having a new intervention available against this disease, which is a huge burden on the health and economical growth of Africa,” said Dr Abdulla.

Rolling out the vaccine could reduce about 655,000 deaths that occur annually, 85 per cent of which are children under the age of five. This ranks it as one of the highest killer diseases of children under the age of five. Malaria transmitted by mosquitoes records over 200 million episodes every year, 700,000 of which result in death, usually in children under the age of five years.

“A vaccine that can reduce these numbers by half would provide significant public health benefits,” said Dr Njuguna.

According to WHO, one person dies of malaria every 30 seconds in Africa. In East Africa, between 16 and 18 million malaria cases are reported every year, leading to more than 300,000 deaths, of which about 75 per cent occur in pregnant women and in children under five years.

Insecticide-treated bed nets were used alongside the vaccine by 86 per cent of the trial participants. “This demonstrates that RTS,S provides protection beyond the existing malaria control interventions. Follow-up in this Phase III trial will continue and is expected to provide more data for analysis to better understand the different findings between the age categories,” said Dr Njuguna.

Healthy partnership

The vaccine trials are being conducted under the partnership of GlaxoSmithKline (the vaccine developer) and PATH Malaria Vaccine Initiative (MVI), with grant funding of over $200 million from the Bill & Melinda Gates Foundation.

“The ability of this vaccine to protect children from severe malaria for 18 months makes it a very promising potential public health tool for the developing world,” said Dr Njuguna.

There was no increase in overall reporting of serious adverse effects between the infants vaccinated with the RTS,S malaria vaccine candidate and infants in the control group.

Two new cases of meningitis were reported in the 6-12 week-old infant age category in addition to the nine reported last year; one in the RTS,S group and one in the control vaccine group. Further analysis revealed a bacterial cause of the meningitis in seven of the 11 cases.

However, while the RTS,S vaccine represents an attempt that is furthest along in clinical trials of more than 25 years, more than 30 other studies are ongoing with researchers working on concurrent vaccines. This, according to Samuel Kariuki, director of the Centre for Microbiology Research (CMR)- KEMRI, is because the malaria parasite has different stages in its lifecycle and multiple species of malaria have a unique lifecycle, unique biochemical structure and different defences against the immune system.

“These separate vaccines are being developed for different species, targeting different stages of their lifecycle. In the end all these will be combined into one, for a more effective malaria vaccine,” said Dr Kariuki.

Malaria still remains a significant global disease burden with the majority of deaths occurring in sub-Saharan Africa.

In East Africa, Kenya, Uganda and Tanzania have high rates of malaria than Rwanda and Burundi, which are highlands.

A WHO malaria report indicates that in Uganda, clinically-diagnosed malaria cases account for up to 40 per cent of outpatient visits, up to 20 per cent of all hospital admissions, and up to 14 per cent of all hospital deaths.

The death of children

In Kenya, up to 19,000 children under the age of five years die of malaria annually and it is estimated that 84 per cent of Kenyans under the age of 15 years are at risk of contracting malaria. A third of all clinical visits are malaria cases of people under the age of 15 years.

Malaria drugs resistance is beginning to be the major threat to the fight against the disease and the rates of resistance are increasing.

The malaria parasite — plasmodium falciparum — is developing resistance to drugs like artemesinin and chloroquine.

Chloroquine was an effective malaria drug that lasted for 50 years. However, it was misused for malaria prevention and ordinary fever, and even mixed with cooking salt, which caused the malaria parasite to become resistant to the active ingredient and it was banned for use by WHO.

The latest Artemisinin-based combination therapies (ACTs), for treating non-complicated malaria as recommended by WHO, initially overcame this, but scientists have reported that resistance to these drugs is starting to develop as well.

Scientists recently found artemisinin-resistant malaria on the border of Thailand and Myanmar and it could spread to India and then Africa as resistance to other antimalarial drugs has done before.

Willis Akwale, the Kenya director of Diseases Prevention and Control said resistance is developing because of the misuse of anti-malarials, such as not completing the treatment course, taking substandard drugs or self administration of antimalarials.

“Most generic drugs are affordable and easily available from chemists and it is not easy to differentiate between genuine and fake drugs,” said Dr Akwale.

A recent study carried out by researchers from Fogarty International Centre at the National Institutes of Health (NIH) in the US, in Southeast Asia and sub-Saharan Africa including Kenya, Rwanda, Tanzania and Uganda showed that one third of the antimalarial drug samples in sub-Saharan Africa failed chemical testing for containing too much or too little of the active ingredient — potentially encouraging drug resistance.

However, the risk of deaths caused by malaria in several African countries have been scaled up and control efforts in countries such as Zambia, Tanzania, Kenya, and Ethiopia decreased between 2000 and 2010 according to a WHO report.

Kenya Director of Public Health and Sanitation Shahnaz Sharif said that malaria control efforts have been scaled up in the region and the Kenyan government has put in place various simple preventive strategies such as free distribution of mosquito nets, use of insect repellants, insecticides and drug therapy, which have been successful for both treatment and prevention. “These interventions have decreased malaria-related deaths,” said Dr Sharif.

WHO launched a T3 (Test, Treat, Track) initiative in April to reinforce the fight against the disease in malaria-endemic countries among them Kenya, Uganda and Tanzania. The T3 initiative is focused on adopting a system of diagnostic testing and antimalarial treatment and creating a strong surveillance web.
In the T3 initiative every suspected malaria case is tested; every confirmed case is treated with a quality-assured anti-malarial medicine; and the disease is tracked through timely and accurate surveillance systems to guide policy and operational decisions.
It is estimated that 50 per cent of households in sub-Saharan Africa have at least one mosquito net.
Early this year, the African Leaders Malaria Alliance (Alma) recognised Benin, Burundi, Cameroon, Kenya, Mozambique, Rwanda, and Tanzania for removing all taxes and tariffs on malaria-related commodities, banning dangerous monotherapy treatments, and making significant progress on malaria control.

Real challenges

Liberian President Ellen Johnson-Sirleaf, the chair of Alma, said that the malaria campaign has made significant progress, but faces real challenges in terms of funding. “Despite this progress, the current global funding crisis, as evidenced by the postponement of the Global Fund Round 11 – threatens the campaign’s momentum,” said Dr Johnson-Sirleaf.

According to WHO, an estimated five to six billion dollars is needed annually to achieve the malaria targets. In 2010, $1.7 billion was committed to the cause, increasing to $2 billion in 2011. Funding for malaria however decreased in 2012, and is estimated to continue to decrease to $1.5 billion annually by 2015. This is largely through lack of funding for the Global Fund to Fight Aids, Malaria and TB by the international community.

Alma estimates that there is a $3.3 billion gap in funding needed to achieve and sustain universal coverage of essential malaria interventions including artemisinin-based combination therapies, rapid diagnostic tests and long-lasting insecticidal nets up to the end of 2015.

Evidence of the mismanagement of the malaria grant has been reported. The latest being in Uganda where the loss of a $51 million malaria grant from the Global Fund resulted in the July arrest of three Ministry of Health employees and prompted a police investigation into the matter.