RTS,S/AS01 is the most advanced vaccine to prevent malaria. It is safe and moderately effective. A large pivotal phase III trial in over 15 000 young children in sub-Saharan Africa completed in 2014 showed that the vaccine could protect around one-third of children (aged 5–17 months) and one-fourth of infants (aged 6–12 weeks) from uncomplicated falciparum malaria. The European Medicines Agency approved licensing and programmatic roll-out of the RTSS vaccine in malaria endemic countries in sub-Saharan Africa. WHO is planning further studies in a large Malaria Vaccine Implementation Programme, in more than 400 000 young African children. With the changing malaria epidemiology in Africa resulting in older children at risk, alternative modes of employment are under evaluation, for example the use of RTS,S/AS01 in older children as part of seasonal malaria prophylaxis. Another strategy is combining mass drug administrations with mass vaccine campaigns for all age groups in regional malaria elimination campaigns. A phase II trial is ongoing to evaluate the safety and immunogenicity of the RTSS in combination with antimalarial drugs in Thailand. Such novel approaches aim to extract the maximum benefit from the well-documented, short-lasting protective efficacy of RTS,S/AS01.

Background

RTS,S is the product of a research collaboration between the pharmaceutical company GSK and the Walter Reed Army Institute of Research (WRAIR) which started in 1984 [1]. WRAIR scientists had extensive experience with the immunogenic properties of the circumsporozoite protein (CSP) of Plasmodium falciparum, while the GSK scientists had expertise in hepatitis B virus (HBV) constructs based on the recent development of a HBV vaccine. The genetic sequences coding for CSP were fused with sequences coding for the hepatitis B surface protein and this chimeric gene was expressed in yeast cells (Saccharomyces cerevisiae). The name RTS,S derives from the CSP repeat region (R), the additionally included T-cell epitopes (T), the HBV surface antigens (S) fused to the CSP proteins, which are assembled with unfused copies of the HBV S antigens. The limited immunogenicity of RTS,S on its own suggested a need for a strong adjuvant system (AS). During extensive studies of various formulations of such systems, the liposomal formulation AS01 was found most promising and combined with RTS,S [1]. The molecular characteristics of this vaccine and the challenges to elicit an appropriate immune response have been recently described in detail [1,2]. This perspective describes the potential future public health use of this vaccine.

Clinical trials

Following a series of trials which proved the safety, immunogenicity, and limited protective efficacy of the vaccine candidate, a large, pivotal, multi-country phase III trial evaluated the safety and efficacy of RTS,S/AS01 in sub-Saharan Africa during 2009 and 2014 [3]. Two groups of participants, 6537 infants (6–12 weeks) and 8922 young children (5–17 months), were randomised into the three arms of the trial: (a) three doses of RTS,S/AS01 at monthly intervals, (b) three doses of RTS,S/AS01 plus a booster at month 20, or (c) a comparator vaccine (rabies or meningococcal vaccine). The vaccine efficacy against uncomplicated falciparum malaria in children was 36.3% (95% CI 31.8–40.5) and in infants 25.9% (95% CI 19.9–31.5) after three doses plus a booster dose. Without booster, the vaccine efficacy was lower in both age groups. The efficacy against severe malaria was slightly but significantly lower than that against uncomplicated malaria. Overall, the vaccine was considered safe. The only exception was meningitis, which was reported more frequently in the vaccine groups compared with the control group. Causative agents of the meningitis episodes included meningococcus, pneumococcus, and Haemophilus influenzae. Fifteen of the 22 cases were reported from a single site. The meningitis cases occurred at variable times after vaccination. These observations suggest that there was no causal relationship between vaccine administration and meningitis episodes. The meningitis rates in vaccinated children were similar to background rates, while the observed rates in the control population were lower than expected. It has been hypothesised that the observed imbalance between vaccinated and unvaccinated study participants could be due to the protection induced by the control vaccines (meningococcal and rabies vaccines) [4,5]. Another safety signal was a higher all-cause mortality following vaccination with RTS,S/AS01 in girls [mortality ratio (MR), 1.91; 95% CI 1.30–2.79] but not in boys (MR 0.84; 95% CI 0.61–1.17) in both age groups. Whether this observation is dose related as in the high-titre measles vaccines requires further study.

Two important studies have helped to understand the performance of RTS,S/AS01. In the first study, Olotu et al. [6] followed a group of 223 children randomly selected to receive RTS,S/AS01 and a control group of 224 children which had been recruited for a phase II trial in 2007 and followed this cohort over 7 years. Not only did they find that the initial vaccine protection wanes over the follow-up period, but the vaccinated children caught up with the controls and had ultimately a similar number of malaria episodes over the entire follow-up period. The results strongly suggested that a booster dose is required to maintain the vaccine protection to malaria. In the second study, Neafsey et al. [7] investigated whether the vaccine efficacy was specific to certain parasite genotypes at the CSP locus. Using specimens and data from the aforementioned phase III trial, they found that the 12-month cumulative vaccine efficacy in young children was 50.3% (95% CI 34.6–62.3) against clinical malaria in which parasites matched the CSP target when compared with 33.4% (95% CI 29.3–37.2) against mismatched parasites. To reach 50% efficacy at 12 months under waning protection, the initial protection after vaccination has to be substantially higher. A close look at Figure 1 suggests that the initial vaccine protection against matched parasite strains may be close to 100% and against mismatched strains the protection is over 50% for 200 days after dose 3.

Cumulative efficacy of RTS,S/AS01 over time.

Figure 1.
Cumulative efficacy of RTS,S/AS01 over time.

Cumulative vaccine efficacy over time [7].

Figure 1.
Cumulative efficacy of RTS,S/AS01 over time.

Cumulative vaccine efficacy over time [7].

Regulatory approval

A critical milestone in the development of RTS,S/AS01 was reached when the European Medicines Agency (EMA), the equivalent of the Federal Drug Administration in the U.S.A., ‘adopted a positive scientific opinion’ for RTS,S/AS01 under Article 58 on 24 July 2015 [8]. Regulatory agencies in countries outside the EU especially malaria endemic countries with limited resources to evaluate a complex dossier such as the RTS,S's can reference the EMA decision should they be inclined to approve the vaccine. Essential policy recommendations are, however, not made by EMA but by the WHO. Two expert WHO committees (SAGE and MPAC) were convened in October 2015, which concluded that due to many uncertainties, the results from a very large trial with an adequate duration of follow-up would have to be reviewed before the roll-out of the vaccine can be recommended.

Next steps

Based on the findings from the phase III trial, the original funder of the earlier trials (the Bill and Melinda Gates Foundation) was no longer interested in paying for the continued development of RTS,S/AS01 despite a positive scientific opinion from EMA. By the end of 2015, the RTS,S development team, consisting mostly of Malaria Vaccine Initiative (MVI) and the vaccine producer GSK, were forced to accept either the end of the development of their vaccine candidate or find a new group of donors to finance the trials needed to provide the data requested by the expert committees. By November 2016, MVI and GSK announced that more than USD $50 Mio had been pledged by a group of donors (GAVI, UNITAID, and Global Fund) [9]. In March 2017, the outline of the RTS,S Malaria Vaccine Implementation Programme (MVIP) was presented to MPAC [9]: 60 clusters with 4000 children per cluster (60 * 4000 = 240 000) will be randomised in three countries each. Children will be vaccinated at age 5 months with subsequent doses after 1 and 2 months and a booster dose at the second birthday of the child. The trials assess the operational feasibility of RTS,S/AS01 roll-out when it is provided through the expanded programme of immunisations (EPI), the impact of RTS,S/AS01 on all-cause child mortality (by gender), malaria-specific mortality, and severe malaria and the frequency of adverse events following immunisation, with an emphasis on meningitis and cerebral malaria. In addition to the main trial, several smaller trials will be added to explore safety and immunogenicity aspects in greater detail. The trials are planned to start in mid-2018 in Ghana, Kenya, and Malawi.

The scope of the proposed MVIP is impressive, but the fixation on RTS/S administration within the EPI schedule is puzzling and probably misguided from the epidemiological point of view. The epidemiology of falciparum malaria has changed significantly since the inception of the RTS,S development programme 30 years ago [1012]. Today, the youngest children in sub-Saharan Africa no longer carry most of the disease burden. Instead, children in school age are increasingly at risk. Adding RTS,S to the EPI schedule may be rational from the logistic and economic point of view since the EPI infrastructure is robust and functioning in many malaria endemic sub-Saharan African countries. Adding RTS,S/AS01 to the expanded programme of childhood vaccinations allows accurate estimations of vaccine demand resulting in maximum market efficiency. Notwithstanding these arguments, vaccinating children too young to be at high risk for malaria will not achieve optimal results considering the short-term protection by the vaccine.

One project which is addressing this age discrepancy is the proposed addition or replacement of Seasonal Malaria Chemoprophylaxis (SMC) with seasonal malaria vaccinations [13]. SMC is recommended for the geographically defined regions where there is a distinct malaria season no longer than 4 months. In 2012, it was recommended that SMC with sulfadoxine/pyrimethamine (SP) combined with amodiaquine (AQ) should be administered to children under 5 years at monthly intervals for 3 or 4 months in areas of sub-Saharan Africa where malaria transmission is highly seasonal and the parasites remain sensitive to AQ/SP [14]. Greenwood et al. [13] have suggested the inclusion of RTS,S vaccinations into SMC. Such a programme would, in the first year, vaccinate children three times in monthly intervals, perhaps in combination with AQ/SP administrations, and in subsequent years provide a booster at the onset of the malaria season. To test this idea, a trial in 6000 young children is being conducted in Burkina Faso and Mali. The advantage of the strategy is that it can be added into a pre-existing infrastructure, SMC in this case. The initial high efficacy of RTS,S/AQ will likely protect children during periods when AQ/SP blood levels are too low to kill P. falciparum.

It is doubtful that seasonal vaccinations of children will make an impact on malaria transmission. The proportion of children under 5 in sub-Saharan Africa is roughly 8% of the total population [15]. Even if malaria transmission in children under 5 would completely stop, some transmission would continue in the remaining 92% of the population. When SMC was extended to children up to 10 years of age, a modest indirect protection (herd effect 26%; 95% CI 18–33%) was observed in one study in Senegal [16].

Meanwhile, the first-line antimalarials, artemisinin combination therapies, are losing efficacy due to resistance. The only way to stop the spread of multidrug-resistant P. falciparum strains is the complete interruption of malaria transmission in foci in SE Asia. In the Greater Mekong Subregion (GMS), very large investments have so far failed to stop the spread of resistant strains [17]. Universal access to the available control tools, such as long-lasting impregnated bednets and early diagnosis and treatment, has dramatically reduced the prevalence of falciparum malaria, but low-level transmission is ongoing and outbreaks can flare up transmission in a very short time. Mass drug administrations (MDAs) to interrupt malaria transmission using dihydroartemisinin/piperaquine and primaquine are being evaluated in the GMS [18]. Preliminary findings suggest that after an initial reduction in parasite prevalence, rates can return to pre-intervention levels perhaps due to incomplete clearing of the subclinical parasite reservoir and parasite re-importation. Adding mass vaccination campaigns to MDA may extend the short-lasting protection afforded by the drug administration sufficiently long to interrupt transmission. Such a combined mass drug and vaccine administration project is planned by our group (MORU) for the GMS. The first step in this project consisting of the co-administration of RTS,S/AS01 with dihydroartemisinin/piperaquine and a single low-dose primaquine in healthy, adult Thai volunteers is currently under way in Mahidol University, Bangkok. If this co-administration study can demonstrate the safety and immunogenicity of the vaccine without affecting satisfactory drug levels, the next step will be a large individually randomised trial to demonstrate the protection and safety in healthy adult Asian volunteers. If RTS,S/AS01 is found to be as safe and at least as protective as in earlier trials, a cluster randomised trial is planned to assess the effect of combined MDA with mass vaccinations of entire village populations before regional roll-out of combined drug and vaccination campaigns can be considered.

Summary

RTS,S/AS01 is the first malaria vaccine with substantial protective efficacy acknowledged by a regulatory agency. The highest protective efficacy of the vaccine has been reported during the initial months after the third dose. The extension of the protection throughout the period, when people are at high risk for falciparum malaria, may require annual booster doses. Yet, there are currently no data whether repeated boosting translates into extended protection. The major programme to roll out RTS,S/AS01 aims to add the vaccine to the EPI schedule for African children, which is pragmatic but not tailored to the strength of the vaccine. Targeting select age bands such as children under 5 is likely to provide individual protection, but is unlikely to make a major impact on malaria transmission. Surprisingly, there are no data on the safety, immunogenicity, and protective efficacy of RTS,S/AS01 in Asians despite the urgent need for a malaria vaccine to eliminate multidrug-resistant falciparum malaria. One way to maximise the benefits of the short but powerful protection afforded by the vaccine would be to vaccinate entire, geographically defined populations in combination with other control activities in regions with low P. falciparum prevalence such as SE Asia. The period of high protection may suffice to eliminate the regional subclinical parasite reservoir without the risk of immediate re-infection and interrupt transmission permanently.

Abbreviations

     
  • AQ

    amodiaquine

  •  
  • AS

    adjuvant system

  •  
  • CSP

    circumsporozoite protein

  •  
  • EMA

    European Medicines Agency

  •  
  • EPI

    expanded programme of immunisation

  •  
  • GMS

    Greater Mekong Subregion

  •  
  • HBV

    hepatitis B virus

  •  
  • MDA

    mass drug administrations

  •  
  • MPAC

    Malaria Policy Advisory Committee

  •  
  • MVI

    Malaria Vaccine Initiative

  •  
  • MVIP

    Malaria Vaccine Implementation Programme

  •  
  • SAGE

    The Strategic Advisory Group of Experts (SAGE) on Immunization

  •  
  • SMC

    Seasonal Malaria Chemoprophylaxis

  •  
  • SP

    sulfadoxine/pyrimethamine

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

References

References
1
Cohen
,
J.
,
Nussenzweig
,
V.
,
Nussenzweig
,
R.
,
Vekemans
,
J.
and
Leach
,
A
. (
2010
)
From the circumsporozoite protein to the RTS,S/AS candidate vaccine
.
Hum. Vaccines
6
,
90
96
2
Long
,
C.A.
and
Zavala
,
F
. (
2016
)
Malaria vaccines and human immune responses
.
Curr. Opin. Microbiol.
32
,
96
102
3
RTS,S Clinical Trials Partnership
(
2015
)
Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial
.
Lancet
386
,
31
45
4
Gessner
,
B.D.
,
Knobel
,
D.L.
,
Conan
,
A.
and
Finn
,
A.
(
2017
)
Could the RTS,S/AS01 meningitis safety signal really be a protective effect of rabies vaccine?
Vaccine
35
,
716
721
5
Gessner
,
B.D.
,
Wraith
,
D.C.
,
Finn
,
A.
(
2016
)
CNS infection safety signal of RTS,S/AS01 and possible association with rabies vaccine
.
Lancet
387
,
1376
6
Olotu
,
A.
,
Fegan
,
G.
,
Wambua
,
J.
,
Nyangweso
,
G.
,
Leach
,
A.
,
Lievens
,
M.
et al. 
(
2016
)
Seven-year efficacy of RTS,S/AS01 malaria vaccine among young African children
.
N. Engl. J. Med.
374
,
2519
2529
7
Neafsey
,
D.E.
,
Juraska
,
M.
,
Bedford
,
T.
,
Benkeser
,
D.
,
Valim
,
C.
,
Griggs
,
A.
et al. 
(
2015
)
Genetic diversity and protective efficacy of the RTS,S/AS01 malaria vaccine
.
N. Engl. J. Med.
373
,
2025
2037
8
European Medicines Agency
(
2015
)
First Malaria Vaccine Receives Positive Scientific Opinion from EMA
.
EMA/CHMP/488348/2015
.
Press_Office
,
London
9
Schellenberg
,
D.
and
Hamel
,
M.
(
2017
)
mpac-mar2017-rtss-update-session2-presentation
. http://wwwwhoint/malaria/mpac/mpac-mar2017-rtss-update-session2-presentationpdf?ua=1
10
Gosling
,
R.
and
von Seidlein
,
L.
(
2016
)
The future of the RTS,S/AS01 malaria vaccine: an alternative development plan
.
PLoS Med.
13
,
e1001994
11
Ceesay
,
S.J.
,
Casals-Pascual
,
C.
,
Erskine
,
J.
,
Anya
,
S.E.
,
Duah
,
N.O.
,
Fulford
,
A.J.C.
et al. 
(
2008
)
Changes in malaria indices between 1999 and 2007 in The Gambia: a retrospective analysis
.
Lancet
372
,
1545
1554
12
O'Meara
,
W.P.
,
Bejon
,
P.
,
Mwangi
,
T.W.
,
Okiro
,
E.A.
,
Peshu
,
N.
,
Snow
,
R.W.
et al. 
(
2008
)
Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya
.
Lancet
372
,
1555
1562
13
Greenwood
,
B.
,
Dicko
,
A.
,
Sagara
,
I.
,
Zongo
,
I.
,
Tinto
,
H.
,
Cairns
,
M.
et al. 
(
2017
)
Seasonal vaccination against malaria: a potential use for an imperfect malaria vaccine
.
Malar. J.
16
,
182
14
WHO
(
2012
)
Policy Recommendation: Seasonal Malaria Chemoprevention (SMC) for Plasmodium falciparum Malaria Control in Highly Seasonal Transmission Areas of the Sahel Sub-Region in Africa
.
World Health Organization
,
Geneva
. http://wwwwhoint/malaria/publications/atoz/who_smc_policy_
15
PopulationPyramid.net.
(
2017
)
Population pyramid Africa 2016
. https://wwwpopulationpyramidnet/africa/2016/
16
Cissé
,
B.
,
Ba
,
E.H.
,
Sokhna
,
C.
,
NDiaye
,
J.L.
,
Gomis
,
J.F.
,
Dial
,
Y.
et al. 
(
2016
)
Effectiveness of seasonal malaria chemoprevention in children under ten years of age in Senegal: a stepped-wedge cluster-randomised trial
.
PLoS Med.
13
,
e1002175
17
Imwong
,
M.
,
Suwannasin
,
K.
,
Kunasol
,
C.
,
Sutawong
,
K.
,
Mayxay
,
M.
,
Rekol
,
H.
et al. 
(
2017
)
The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study
.
Lancet Infect. Dis.
17
,
491
497
18
von Seidlein
,
L.
and
Dondorp
,
A.
(
2015
)
Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance
.
Expert Rev. Anti-Infect. Ther.
13
,
715
730