phase 3 trial RTS/AS01

1. JOURNAL CLUB
7/9/2022
Dr. Rasika Deshmukh

2. Journal : PLOS Medicine
Published : July 29,2014
Randomized controlled trial ,Double blinded
Funded by: GSK Biologicals SA and the PATH Malaria
Vaccine Initiative (MVI)
Impact factor:11.61
Citation index :331

3. Duffy, P.E., Patrick Gorres, J. Malaria vaccines since 2000: progress, priorities, products. npj
Vaccines 5, 48 (2020). https://doi.org/10.1038/s41541-020-0196-3

4. RTS,S
• the most advanced PEV
• R- P. falciparum CSP fragment comprising central
repeat
• T- C-terminal regions (containing T cell epitopes,
hence “T”)
• S- hepatitis B surface antigen
• S- RTS is expressed in yeast that also carry
hepatitis B “S” expression cassettes, and thus
synthesize S and RTS polypeptides that
spontaneously co-assemble into mixed
lipoprotein particles (or “RTS,S”) with the CSP
fragment on their surface
Duffy, P.E., Patrick Gorres, J. Malaria vaccines since 2000: progress, priorities, products. npj
Vaccines 5, 48 (2020). https://doi.org/10.1038/s41541-020-0196-3

5. Children from 6 week to 17 months
0.5 ml intramuscular
3 doses at montly interval
Booster dose 18 months after 1st dose
WHO approved
FDA approval pending

6. Introduction
Plasmodium falciparum estimated
• cases:207 million cases of malaria
• deaths 627,000
• mostly in young children
• sub-Saharan Africa
• Newer problems like emerging insecticide and
drug resistance

7. Phase 1 outcome
targets the preerythrocytic stage of P. falciparum
induces humoral and cellular immune responses to the
circumsporozoite protein
identified as a potential candidate for further development

8. Phase 2 outcome
Phase 3
AS01
well tolerated
immunogenic
Efficacious
safe

9. • Randomized, controlled, double blind trial of the candidate
malaria vaccine
•GSK and all coinvestigators remain blinded.
•External statisticians run the analyses.
• conducted at 11 sites in seven African countries
•Target population: children and young infants
•Duration: March 27, 2009, through January 31, 2011
•Intervention: RTS,S/AS01
•Controls: Comparator vaccine
•Outcome: Trial is ongoing

10. Hypothesis
• Vaccination in infants and children reduces the
incidence of malaria
AIM
• to evaluate VE, safety, and immunogenicity
during an average period of 49 mo (range: 41–
55 mo) and 41 mo (range: 32–48 mo) after the
first dose of study vaccine in children and
young infants respectively.

11. Inclusion criteria Exclusion criteria
•Infants aged 6–12 week
•Children aged 5–17 months
•Children with a moderate or severe
illness;
•Major congenital defect;
•Malnutrition requiring hospitalization;
•Hemoglobin concentration ,5.0 g/dl, or
8 g/dl with clinical signs of
decompensation;
•History of atypical febrile seizures;
•Neurological disorder;
•WHO stage III or stage IV HIV disease
at the time of presentation

12. Study design
CONSORT diagram of infants at enrollment followed until 18 mo post-vaccination.

13. Study design
CONSORT diagram of children at enrollment followed until 18 mo post-vaccination.

14. Study design & Randomization
15460 young infants and children
Infants:6537
Children:8923
RTS,S/AS01 group
Primary doses
with booster
RTS,S/AS01
group
Primary doses
without booster
Control grp
Children: Rabies vaccine (Sanofi
Pasteur)
Infants: Meningococcal C conjugate
vaccine (Novartis)
Randomly assigned in
1:1:1 ratio

15. Surveillance for Clinical and Severe Malaria
• passive surveillance
• Clinical malaria was defined as an illness
accompanied by a temperature ≥37.5 °C
• P. falciparum asexual parasitemia (˃5,000
parasites/mm3 ) or
• as an algorithm-defined case of severe malaria

16. Safety Surveillance
• Data on serious adverse events (SAEs) were
collected by passive surveillance
• clinical evidence based
• not bound by stringent laboratory or
diagnostic criteria.
• Autopsies were conducted on deaths that
occurred outside a hospital.

17. Immunogenicity
• Anti-circumsporozoite (anti-CS) antibodies
were measured by ELISA in the first 200
participants in each age category at each
study site at enrollment and 1 mo after the
third dose of vaccine.
• The threshold for a positive titer was 0.5
EU/ml

18. Laboratory and Radiologic Procedures
• All blood smears were read by two independent
microscopists, and parasite densities were
determined using standardized procedures.
• Discrepant findings were resolved according to a
formal algorithm.
• Standardized, automated biochemical and
hematological methods were used.
• Standard microbiology methods for blood and
CSF culture were followed using automated
Bactec incubators and pediatric bottles (Bactec
BD Diagnostic Systems).
• Rigorous external quality assurance process was
implemented

19. Results
Vaccine Efficacy in Children Vaccine Efficacy in Infant
incidence of all
episodes of clinical
malaria
RTS,S/AS01 group : 0.69/person-
year
RTS,S/AS01 group : 0.71/person-
year
control group : 1.17/person-year control group : 0.92/person-year
VE 46% 27%
VE, ITT 45% 27%
Reduction in incidence of clinical malaria after 3 doses in VE/VE,ITT
VE VE,ITT VE VE, ITT
1-6 months 68% 60% 47% 44%
7-12 months 41% 41% 23% 23%
13-18 months 26% 28% 12% 13%
Clinical malaria

20. Results
Vaccine Efficacy in Children Vaccine Efficacy in Infant
VE 36% 15%
VE, ITT 34% 8%
Hospitalization due to malaria
VE 42% 17%
VE,ITT 41% 13%
Hospitalization due to all cause
VE 19% 6%
VE,ITT 19% 5%
Severe malaria
VE waned off over period of time in children and infants

21. Results
• Immunogenicity
Childrens Infants
Geometric mean titre 348 to 787 EU/ml 117 to 335 EU/ml
Higher Lower
Higher the titer, lower is the incidence

22. Figure 20. Graphical representation of anti-CS geometric mean titers, vaccine efficacy,
and malaria incidence (per-protocol population).

23. Results
• Mortality
Children Infants
Total 107 117
RTS,S Group 74 83
Control Group 33 34

24. Results
Safety
• SAEs were less frequent in the children
vaccinated with RTS,S/ AS01 than in control
children: 18.6% versus 22.7%

25. Results
17 children
16 RTS,S group
10 unidentified
pathogen
4 Meningococcus
1 Pneumococcus
1 H.influenza
1 control group
1 unidentified
pathogen
6 children died :5 RTS,S group and 1 control group
Meningitis

26. Results
12 infants
9 RTS,S group
3 unidentified
pathogen
4 Pneumococcus
3 Salmonella
3 control group
2 unidentified
pathogen
4 infant died :2 RTS,S group and 2 control group
Meningitis

27. Discussion
• protection against clinical and severe malaria,
among children aged 5–17 months at first
vaccination
• VE against clinical malaria was 40% or higher in
each setting but varied significantly between
sites
• VE was lower in young infants.
• Severe malaria was more frequent among
young infant RTS,S/AS01 recipients compared
with controls
• young infants with detectable anti-CS
antibodies at enrollment had a lower post-
vaccination anti-CS response

28. Discussion
• No evidence that priming with hepatitis B
vaccine in children explained their enhanced
anti-CS antibody response
• VE waned over time in both young infants and
children
• Incidence of SAEs was similar in participant in
each group
• No impact of RTS,S/ AS01 on overall mortality,
incidence of hospitalized pneumonia or
septicemia

29. limitations
• presence of moderate anemia at enrollment, >>reflect
malaria exposure at the individual level >>negatively
associated with VE
• Incidence of malaria correlation with genetic and
environmental factors, nutritional factors??
• no correlation found between VE and transmission
• Differences in anti CS antibody GMT across sites??
• vaccine interfered with the acquisition of natural
immunity??
• Impact of maternal antibody ?? Not thoroughly studied
• Give at time EPI, immune interference of other vaccines??

30. conclusion
• During 18 mo of follow-up, RTS,S/AS01
prevented many cases of clinical and severe
malaria across the 11 sites in the trial
• Despite its lower efficacy in young infants,
RTS,S/AS01 prevented a substantial number of
cases of clinical malaria in young infants.
• reductions in clinical cases on this scale as a
result of vaccination with RTS,S/AS01
• major public health impact.

31. Thank you