1. Deluxini Sundralingam
Saifuddin Syed

2.  Mosquito-borne disease
 Transmitted by inoculation of plasmodium parasite sporozoite
stage
 Sporozoites invade hepatocytes, transform into liver stages
 Subsequent liver-stage development leads to release of
pathogenic merozoites
 http://www.youtube.com/watch?v=VfxjJVLKWZw

3. There are five species of Plasmodium protozoa
which infect humans via mosquitos:
 P. falciparum
 P. vivax
 P. malariae
 P. ovale
 P. knowelsi

4. • 3 billion people are at risk of infection
• 225 - 300 million cases of malaria occurring annually
• 780,000 - 1 million attributable deaths worldwide
• Deaths occur in young children and pregnant women
in developing countries
• Extraordinary cost in terms of human morbidity,
mortality and economic burden

6.  3 major control measures exist and have been widely
used in the last decade in an effort to reduce or
control malaria
 Artimisinin based Combination Therapy (ACT)
 Long-lasting insecticidal nets (LLIN) or Insecticide
Treated Nets (ITN)
 Rapid diagnostic tests

7.  Quinine
 Chloroquine
 Amodiaquine
 Pyrimethamine
 Proguanil
 Sulfonamides
 Mefloquine
 Atovaquone
 Primaquine

8.  ACT has limiting factors:
 adopting policies,
 limited knowledge on safety in pregnancy,
 and the imbalance between demand and supply
 Recently WHO has recommended that a ban be placed
on oral artimisinin bases monotherapies due to
emergence and spread of drug resistance.
 LLIN/ITN
 There is also growing resistance to the insecticide used
on nets; 45 countries have identified resistance to one
of the four classes of insecticides used

9.  Shortfalls of control measures and continuing
prevalence of malaria, the focus has shifted
 WHO identified vaccines as a cost effective method
to reduce the burden of this disease
▪ cost-effective analysis revealed the economic benefit of
reducing or eliminating malaria is enormous
▪ cost effectiveness of vaccines in public health indicated an
economical return in improved health per dollar spent

10.  Assumptions for Vaccines against Malaria
▪ Antibody-mediated protection
▪ Cell-mediated immune responses of the T-cells
▪ Subsequent infections would recall both types of immune
responses

11.  The focus of the presentation will be on RTS,S
 Devloped in partnership by GSK, MVI-PATH,
Bill and Melinda Gates Foundation, Academic
Instituions and African Countries.
 GSK announced that the eventual price of RTS,S
will cover the cost of manufacturing, and a 5%
return to be reinvested in R&D for second-
generation malaria vaccines or vaccines against
other neglected tropical diseases.

12.  Malaria parasite has a complex lifecycle; there
are 3 areas of lifecycle development that are
the focus of vaccine development research:
 Pre-erythrocytic stage
 Asexual erythrocytic stage (blood stage)
 Sporogonic cycle (sexual stage)

15.  Circumsporozoite protein (CS)
 A hybrid vaccine was created which combined an independent T-cell epitope along with
the P. falciparum CS protein and hepatitis B surface antigen; hybrid was called
R16HBsAg
 R16HBsAg: included 16 tandem repeats of the epitope of the P. falciparum CS protein
fused with the pre-S2 region of HBsAg
 Aluminum salts (adjuvants) + R16HBsAg increased antibody response to the CS
epitome in mice and rabbits
 Clinical trials of R16HBsAg showed that R16HBsAg was safe and immunogenic
 All the participants of the trial were given doses at monthly intervals; 20 displayed anti-
CS antibody response, 17 displayed antibody titer of ≥ 1:1200, and 13 with anti- CS
antibody response 10 months after vaccination

16.  R16HBsAg was later redesigned to include T- and B-
cell epitopes from the C-terminus of the CS protein and
was renamed to RTS,S
 Novel particle was named RTS:
 ‘R’ for the CS repeats,
 ‘T’ for T-cell epitopes and
 ‘S’ for HBsAg.
 ‘S’ for genetically transformed yeast strain used to produce
these antigens, expressed two polypeptides, RTS and S,
with a resulting 1:4 ratio

17.  GSK developed and own the proprietary rights on the adjuvant systems (AS)
 5 different types of adjuvants used in the formulation RTS,S AS01, AS02, AS03, AS04 and
Alum
 Alum and AS04 contain aluminum salts; which are safe and prolong immune stimulation via
recruitment of antigenpresenting cells (APCs)
 AS04, AS02 and AS01 also contain 3-deacylated monophosphoryl lipid A (MPL) MPL triggers
immunity, humoral and cellular immune response by promoting the maturation of APCs by
acting upon TLR-4
 AS03 and AS02 use oil (squalene)-in-water-based emulsion; the oil phase contains a unique
substance DL-a-tocopherol. DL-a-tocopherol enhances antigen-specific response, early
eosinophil and neutrophil migration, antigen loading in monocytes, and affect cytokine
production
 AS02 and AS01 contain the saponin QS21; QS21 stimulates antibody and CTL responses to
antigens

18.  Late 1990s the first RTS,S field trials were conducted in adults in Gambia
and Kenya.
 In the phase II trials RTS,S was combined with AS02A; RTS,S/AS02A,
was found to be safe, well tolerated and immunogenic.
 Before the third vaccination, test group had an increase of twenty fold
concentration of antibodies against the CS protein
 Maintained an increase of tenfold during the following year
 This combination provided heterogeneous protection against strains
other than its original strain
 Overall 34% vaccine efficacy versus parasitic infection,
 During peak malaria transmission season, a fourth round of
RTS,S/AS02A was administered; the result was higher antibody
concentrations and a vaccine efficacy of 47%

19.  The combination of RTS,S/AS01B was found to be superior to
RTS,S/AS02A in humans
 The results found a higher level of antibodies against the CS protein in
patients with RTS,S/AS01B when compared to patients with
RTS,S/AS02A
 It was also demonstrated that those participants administered with the
vaccine had a higher blood concentration of antibodies then the
participants in the control group with and efficacy rate of 30%
 This gave further support for the superiority of the RTS,S/AS01B
formulation and led a decision to evaluate in a paediatric population

20.  Starting in 2001, 2 separate phase I trials began in
paediatric population at risk for sever malaria
 In the phase I trials RTS was combined with AS02A with
different vaccine doses tested for. The trials showed safety,
immunogenicity, and the doses were well tolerated in all
population
 In 2003 phase II trials began in paediatric populations,
 At the 6 month interval, efficacy for first episode of disease
was 30% and efficacy against sever malaria was 57.7%
 At 45 months the population was tested again to reveal
efficacy for first episode of disease was 30.5% and efficacy
against sever malaria was 38.3% while also revealing 25%
reduction in malarial disease

21.  Another 2 trials were setup afterwards to examine
RTS,S/AS02D in infants
 After 3 months trial 1 showed vaccine efficacy of 65.9% and an
overall efficacy against infection at 35.5%
 After 3 months trial 2 showed vaccine efficacy of 65.2% and an
overall efficacy against infection at 41.8%
 Another paediatric formulation was developed and tested for
paediatric population due to its success in adults;
RTS,S/AS01E
 In 2007, clinical trials conducted showed improved safety and
immunogenicity when compares to RTS,S/AS02D
 Over an 8 month period vaccine efficacy for first episode was
reported at 53% and at 15 months was reported to be at 45.8%

22.  Randomized, controlled and double-blinded
 2 age categories : 6 to 12 weeks of age
5-17 months of age
 3 study groups with children
 who received all 3 doses of the vaccine administered at 1-
month intervals and scheduled for a booster dose 18
months after the third dose
 who received the primary vaccination series without a
booster
 control group who received a non-malaria comparator
vaccine.

23.  Reduced clinical episodes of malaria and
severe malaria by half
 Efficacy of RTS,S/AS01 in 2011 and 2012
during 12 months of follow-up
Age Group Severe Malaria Clinical Malaria
6 to 12 weeks of age 36.6% 31.3%
5-17 months of age 47.3% 55.8%

24.  Serious Adverse Events
Age Group RTS,S/AS01 Control Group
6-12 weeks 569/4358 293/2179
5-17 months 1048/5949 642/2974
 Number of Deaths
Age Group RTS,S/AS01 Control Group
6-12 weeks 49 18
5-17 months 56 28
 Among the infants died, only 10 were due to diagnosis of
malaria

25.  Other serious adverse events occurred after
vaccination includes seizures, pyrexia,
myositis and febrile convulsion
 The most frequently reported symptoms were
pain and fever. Overall, RTS,S/AS01 vaccine
was more reactogenic than was control

26.  1 month after the administration of the third
dose of a study vaccine, 99.9% of children and
99.7% of infants in the RTS,S/AS01 group
were positive for anti–circumsporozoite
antibodies

27.  SPf66
 AdCh63/MVA MSP1
 PfSPZ
 MSP3
 GMZ2
 AMA1-C1/Alhydrogel +CPG 7909
 FMP1AS02A

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