Page 64 - The lraternational Journal of the Royal Society of Thailand.indd

The International Journal of the Royal Society of Thailand
Volume XV-2023

sudden halt when the less than stellar results from the first large clinical trials in
African children were announced (Agnandji et al, 2012). Bill was disappointed (Butler
D, 2012). The former closest malaria advisors were replaced with Alan McGill who as
a new head of the malaria programme had the unpleasant task to turn off the funding
for RTS,S/AS01. Despite funding issues, RTS,S received a positive scientific opinion

from a major, stringent regulator, the European Medicines Agency (EMA). While
this assessment was encouraging, major donors including UNICEF require WHO
prequalification to purchase products such as a malaria vaccine. But the relevant

committees in the WHO were not convinced by several aspects in the dossier specifically
the overall impact, safety, and cost effectiveness (WHO, 2015; WHO, 2016). To receive
prequalification the WHO recommended a very large demonstration project (WHO,
2021). With the BMGF and GSK unwilling to fund such a study it took several years
until this project finally took off in Ghana, Malawi, and Kenya, which confirmed that

a four-dose schedule of RTS,S with the adjuvant AS01 was indeed safe and protective
in young children. In July 2022 the WHO finally prequalified RTS,S/AS01, seven years
after EMA had already concluded that RTS,S/AS01 was safe and protective (WHO,

2022). That is a seven-year delay in approval for a vaccine to prevent a disease which
caused more than 600,000 deaths in 2021 alone (WHO, 2022).

An ideal malaria vaccine should be safe and well tolerated, provide life-long
robust protection and be available at millions of doses to be rolled out annually at less
than a dollar per dose. The less-than-ideal RTS,S vaccine is safe and well tolerated but

confers less than complete protection for a limited duration. During the first days and
weeks following RTS,S vaccination protection is over 90% (Neafsey et al, 2015).
Over the following months protection rapidly wanes. In the pivotal trial that led to
licensing, 15,460 children participated in 7 African countries with highly heterogeneous
malaria epidemiology. Over 18 months of follow-up, a three dose regimen of RTS,S/

AS01 conferred 46% protection against clinical malaria in 5 to 17 month old children,
and 27% in 6 to 12 week old infants (RTSS_Clinical_Trials_Partnership, 2014). By the
end of the trial during 38 to 48 months of follow-up vaccine efficacy decreased to 28%

and 18% respectively (RTSS_Clinical_Trials_Partnership, 2015). In 2021, Chandramohan
and Greenwood presented an alternative, more appropriate strategy to optimize
the protection afforded by RTS,S/AS01 (Chandramohan et al, 2021). By combining a
four-dose regimen of RTS,S/AS01 with seasonal malaria chemoprevention (SMC)
administered just before the malaria season, the protective efficacy of the combination

as compared with chemoprevention alone was 63% against clinical malaria, 71% against
hospital admission with severe malaria, and 73% against death from malaria in trial
sites in Mali and neighbouring Burkina Faso.

56 The First Licensed Malaria Vaccines: From RTS,S to R21