•But there are clear benefits, say researchers

By Sola Ogundipe

HOPES of a universal, commercially licensed malaria vaccine this year may have dimmed as the first candidate malaria vaccine to reach phase III clinical trials, though safe, has been found to provide only modest protection for infants.

Results of the RTS,S/AS01 vaccine clinical trial that is being conducted across 11 research centres in Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique and Tanzania, indicate that the vaccine is not as effective at protecting young African children against malaria as was hoped.

The participants were enrolled between March 2009 and January 2011 in the trial, conducted by GlaxoSmithKline, in partnership with the PATH Malaria Vaccine Initiative (MVI) funded by the Bill and Melinda Gates Foundation.

The phase three trial of the vaccine candidate showed a 54 percent reduction in cases of clinical malaria over the first year of follow-up and a 36 percent reduction in clinical malaria over a 48 month period among children vaccinated between 5-17 months old who received four doses of the vaccine. On average across the trial sites, more than 1,700 cases of clinical malaria were averted per 1,000 children vaccinated.

A publication in The Lancet, revealed that in 15,459 infants aged 6–12 weeks and children, 5–17 months,  the reduction in clinical malaria was 26 percent over a follow up period of 38 months.

There is currently no licensed malaria vaccine but at least  20 vaccines are under various stages of development.

According to the World Health Organisation, WHO, malaria vaccines are considered amongst the most important modalities for potential prevention of malaria disease and reduction of malaria transmission.

Early trial results published in 2014 found that the recombinant protein vaccine RTS,S/AS01 was more effective in children than infants, reducing malaria cases in children by almost a half and by just over a quarter in infants at 18 months after vaccination.

• Search for a universal malaria vaccine has been on for several years. The World Health Organisation, WHO, says malaria vaccines are considered amongst the most important modalities for potential prevention of malaria disease and reduction of malaria transmission.

The latest results show that the effectiveness of the vaccine drops over time, although this can be boosted by a booster dose to reduce a third of cases in children at four years from vaccination.

Despite the setback, however, researchers say the vaccine is still worth deploying because millions of children could benefit from vaccination in areas of high transmission.

Brian Greenwood, a researcher in tropical medicine at the London School of Hygiene and Tropical Medicine, who is involved in the trial, noted: “Despite the falling efficacy over time, there is still a clear benefit from RTS,S/AS01. An average 1,363 cases of clinical malaria were prevented over four years of follow-up for every 1,000 children vaccinated, and 1,774 cases in those who also received a booster shot. Over three years of follow-up, an average 558 cases were averted for every 1,000 infants vaccinated, and 983 cases in those also given a booster dose.

“Given that there were an estimated 198 million malaria cases in 2013, this level of efficacy potentially translates into millions of cases of malaria in children being prevented.”

Vaccine worth deploying

A director of the Jenner Institute at the University of Oxford, Adrian Hill, says the assertion that the vaccine may be worth deploying in some settings because it prevented large numbers of uncomplicated cases was controversial.

“There was no impact on malaria mortality and no significant effect on severe malaria: non-significant reductions of just 1 percent and 10 percent were observed in the children and infants studied over the full trial period using a three dose regimen. This is clearly lower than the efficacy of impregnated bed nets,” Hill says.

New evidence of a rebound in malaria susceptibility after vaccination was “worrying”, he adds. “After 20 months, vaccinated children who were not boosted showed an increased risk of severe malaria over the next 27 months compared with non-vaccinated controls.

“It should be possible to make the vaccine more effective in some settings with improved scheduling, but that will probably increase delivery costs substantially,” he argued.

The safety and efficacy of RTS,S/AS01 is being reviewed by the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) under an article 58 procedure, which allows the CHMP to give opinions, in co-operation with the World Health Organisation (WHO), on medicinal products for human use that are intended exclusively for markets outside of the EU.

If a positive opinion is obtained and the vaccine is pre-qualified by the WHO, malaria endemic countries will need to decide whether to license and use the vaccine and, if so, what schedule to use, say the researchers.

The results suggest a malaria vaccine ultimately has a role alongside mosquito nets, indoor spraying, prompt diagnostic testing, effective anti-malarial medicines and other tools in reducing the disease’s impact among children in sub-Saharan Africa.

In April 2015, the WHO issued updated Guidelines for the Treatment of Malaria, recommending the use of Artemisinin-based Combination Therapies (ACTs) and diagnostic testing for all suspected malaria cases to ensure that malaria drugs are used only by those who have the disease.

Vulnerable groups: WHO also recommends that the most vulnerable groups in malaria-endemic areas of sub-Saharan Africa — pregnant women, children under 5, and infants — receive preventive treatment to reduce the risk of malaria infection.

In a related development, a malaria vaccine was 67 percent protective against infection in an early-stage trial involving adults in Kenya, according to a study in Science Translational Medicine. Researchers say the results are encouraging, because many malaria vaccines that work well in the lab  fail to show the same efficacy in the field. But low malaria infection rates in the region at the time of the study  put a damper on the results.

“The vaccine “shows promise, but we can’t know if the vaccine would perform as well in areas where the risk for malaria is high,” said Philip Bejon, an infectious disease researcher at the University of Oxford and a co-author of the study.

The researchers found that the vaccine was safe overall. Blood tests showed that the men built up a strong immune response against infection. In addition, the vaccine provided partial protection — it was 67 percent effective — against infection with the malaria parasite for at least two weeks following vaccination. But because of weather-related fluctuations, the transmission rate of malaria was “much lower than expected” during the study period.

Over the years, researchers, clinical trialists and vaccine developers have been working on many approaches to bring forward the availability of a universal malaria vaccine.

Vaccines take 8-10 years to produce: According the National Malaria Elimination Programme, NMEP, it takes 8-10 years for a vaccine to be fully developed.

The RTS,S/AS01 vaccine is first in line and is undergoing the last stage of trial which is the phase 3. Nigeria is one of the countries where the final stages of the trial was carried out in Jos and Enugu.

Calls for more research into development of indigenous vaccines have made the rounds. Statistics reveal that 97 percent of the Nigerian population is at risk of malaria infection and malaria has remained a major public health problem.

The country harbours an estimated 100 million malaria cases with over 300,000 deaths per year; 29 percent of childhood deaths, 25 percent of infant mortality and 11 percent of maternal mortality due to malaria.