Friday, November 6, 2015

New Study on RTS,S/AS01 Malaria Vaccine Published in The Lancet

LONDON (6 November 2015)—The RTS,S malaria vaccine is predicted to have a significant public health impact and high level of cost-effectiveness across a wide range of settings in sub-Saharan Africa, according to harmonized research from four different mathematical modelling groups published in the November 5th edition of The Lancet. The article titled "Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models"contributes to the scientific evidence being considered by the World Health Organization (WHO), which is assessing the malaria vaccine for use in Africa.

The researchers found that over a 15 year time horizon, an average of 116,500 cases of clinical malaria disease and 484 deaths would be averted for every 100,000 children vaccinated under a four-dose schedule of immunizations at 6, 7.5, 9 and 27 months of age. This translates to approximately 1.2 cases averted per vaccinated child and one malaria death averted for every 200 children vaccinated. These data apply to children living in regions of Africa that experience moderate to high malaria transmission—countries where prevalence rates for the most deadly malaria parasite, Plasmodium falciparum, range from 10 to 65 percent—and assumes a vaccine coverage rate at fourth dose of approximately 70%.

“We took a realistic look at expected coverage of the RTS,S vaccine in a variety of African settings and found it would have significant impact on malaria disease in all but the lowest malaria transmission regions,” said study author Dr. Melissa Penny from the Swiss Tropical and Public Health Institute. “Our numbers indicate that 6 to 29 percent of malaria deaths in children younger than age five could potentially be averted by the vaccine in the areas in which it is implemented, when used alongside other malaria control interventions.”

This is the first modelling study to use final site-specific results of the RTS,S Phase III safety and efficacy clinical trial coordinated by GlaxoSmithKline Vaccines (GSK), conducted at 11 sites in seven African countries, and it accounts for implementation of the vaccine alongside use of long-lasting insecticide-treated bed nets.

There was consensus across the predictions from all four groups that took part in the study, according to the researchers. The participating institutions are Imperial College London (Imperial), the Swiss Tropical and Public Health Institute (Swiss TPH), the Institute for Disease Modeling (IDM) in the United States, and GSK in Belgium.

According to the study authors, public health authorities require these types of impact estimates on malaria disease and deaths to inform vaccine implementation. Models can account for differences between the trial and real-life settings in transmission levels and health care accessibility, and predict RTS,S impact on malaria mortality that was not possible to assess in the trial. Despite progress, malaria remains a leading cause of death in children of all ages in sub-Saharan Africa. The WHO estimated there were 214 million new malaria cases and 438,000 malaria deaths in 2015, the vast majority (190 million malaria cases and 400,000 malaria deaths) in sub-Saharan Africa.


As part of the modelling study, the authors considered a range of possible vaccine prices, from $2 to $10. Compared to current malaria interventions, they found that the vaccine would be cost-effective to implement under an assumed price of USD$5 per dose in areas of moderate and high malaria transmission.

“The cost-effectiveness of RTS,S is similar to what we’ve seen for other recently introduced childhood vaccines,” said Prof. Azra Ghani of Imperial College London, one of the study collaborators. “It also overlaps within the ranges of cost-effectiveness of other malaria control interventions like bed nets and indoor residual sprays. However, it is important that the vaccine is introduced in addition to these other highly cost-effective interventions.”

The authors measured cost-effectiveness in terms of DALYs – disability-adjusted life years. DALYs are a metric used by health economists to compare the impacts of health interventions in populations over time. One DALY is equivalent to one lost year of healthy life. The lower the amount spent per DALY averted, the greater the cost-effectiveness of an intervention.

At a price of $5 per dose the researchers estimated a median cost of $87 per DALY averted for a four-dose vaccine schedule across the range of transmission settings with parasite prevalence 10 to 65%. This cost was estimated to vary depending on the level of malaria transmission found in a particular location – with the vaccine being increasingly cost-effective in areas with a higher malaria burden.

The authors outline that, according to earlier studies, the cost per DALY averted for other malaria interventions indicate averages of $27 for long-lasting insecticide-treated bed nets, $143 for indoor residual spraying, and $24 for intermittent preventative treatment respectively.


Among the limitations of the analysis noted by the researchers is remaining uncertainty in the vaccine efficacy after the four years of follow-up observed in the trial. They also noted that since the Phase III trial of RTS,S was not large enough to test for reduction in deaths from malaria (versus reduction in incidence of malaria cases) and the quality of care provided to participants was high, the modelling studies’ projection of deaths requires further validation during the implementation phase.

“It will be important to continue to track the long-term impact of this vaccine to ensure that the effectiveness predicted by the models is borne out in practice,” said Dr. Caitlin Bever of the Institute for Disease Modeling.

About RTS,S

In early 2014, the large-scale Phase III safety and efficacy trial of the RTS,S/AS01 malaria vaccine was completed at 11 African research sites in seven countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and Tanzania). On a four-dose schedule, vaccine efficacy against clinical malaria was 43.9 percent in children aged 5-17 months and 27.8 percent in infants aged 6-12 weeks over 32 months of follow-up. The vaccine, developed by GSK in partnership with the PATH Malaria Vaccine Initiative, is designed to prevent malaria caused by the P. falciparum parasite in sub-Saharan Africa.

In July, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued a positive scientific opinion for RTS,S under a process called Article 58. In October, the Strategic Advisory Group of Experts on Immunization (SAGE) and Malaria Policy Advisory Committee (MPAC), two independent advisory bodies to the WHO, jointly recommended that pilot implementation of the vaccine be undertaken in African countries to better understand how RTS,S could best be used outside of a clinical trial setting. The WHO is expected to announce its formal policy recommendation for RTS,S by the end of 2015.

Three of the modelling groups received funding from sources that included the Global Good Fund of Bellevue, WA; the PATH Malaria Vaccine Initiative; the Bill & Melinda Gates Foundation; the UK Medical Research Council; and the UK Department for International Development. GSK self-funded their modelling exercise.

About the MRC Centre for Outbreak Analysis and Modelling, Imperial College London

The MRC Centre for Outbreak Analysis and Modelling is a centre at Imperial College London. As the only UK University to focus entirely on science, technology, engineering, medicine and business, Imperial College London offers a critical mass of international research and expertise to improve quality of life for people throughout the world.

About Swiss Tropical and Public Health Institute

The Swiss Tropical and Public Health Institute Swiss TPH is a leading public and global health institution. Its mandate is to contribute to improving the health of populations through excellence in research; health service provision; and education & training. Associated with the University of Basel Swiss TPH has more than 700 employees and students working in 22 countries. Since July 1st Professor Jürg Utzinger is the director of Swiss TPH.

About the Institute for Disease Modeling (IDM)

As part of Intellectual Ventures' Global Good initiative, the Institute for Disease Modeling (IDM) is committed to improving and saving lives in developing countries through the use of quantitative analysis. IDM focuses on creating powerful and innovative disease modeling and data analysis tools and software to help the global health community evaluate the combination of health policies and intervention strategies.