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
5.
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
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)
13.
14.
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
28. 1. Regules, J., Cummings, J., & Ockenhouse, C. (2011). The RTS,S Vaccine Candidate for Malaria. Expert Reviews,
10(5).
2. Agnandji, S., & Lell, B. (2011). First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children. The
New England Journal of Medicine, 365.
3. L, Schwartz and B, Graham.(2012). A Review of Malaria Vaccine Clinical Projects Based on the WHO Rainbow
Table. Malaria Journal 11.11.
4. "PATH Malaria Vaccine Initiative: The need for a vaccine." PATH Malaria Vaccine Initiative. N.p., n.d. Web. 28 Nov.
2012.
5. Geoffrey, T., & Greenwood, B. (2008). Malaria vaccines and their potential role in the elimination of malaria.
Malaria Journal, 7.
6. Mutabingwa , T. (2005). Artemisinin-based combination therapies (ACTs): best hope for malaria treatment but
inaccessible to the needy! Acta Trop, 95(3).
7. WHO (n.d.). Malaria Transmission Blocking Vaccine: an ideal public good. Special Programme for Research &
Training in Tropical Disease.
8. PATH Malaria Vaccine Initiative. (n.d.). Retrieved from http://www.malariavaccine.org/files/MVI-brief-RandD-
strategy-FINAL-web.pdf
9. Moorthy, V., & Ballou, R. (2009). Immunological Mechanisms Underlying Protection Mediated by RTS,S: a review
of the available data. Malaria Journal, 8(312).
10. Milstein, J., & Cárdenas, V. (2010). WHO policy development processes for a new vaccine: case study of malaria
vaccines. Malaria Journal, 9.
11. PATH Malaria Vaccine Initiative: Advocacy fellowship. (n.d.). PATH Malaria Vaccine Initiative. Retrieved from
http://www.malariavaccine.org/preparing-mvaf.php
12. WHO | Malaria. (n.d.). Retrieved from http://www.who.int/mediacentre/factsheets/fs094/en/
13. The role of vaccine in the prevention of malaria « HCDCP. (n.d.). ΚΕΕΛΠΝΟ. Retrieved from
http://www2.keelpno.gr/blog/?p=2178&lang=en
Hinweis der Redaktion
Plasmodium falciparum is the most deadly of the malarial species accounting to over 90% of malaria related deaths [3] and it is the most common cause of morbidity. P vivax is a growing threat in SE Asia
It is estimated that over 3 billion people are at risk of infection [1], with a range of 225 [2] to 300 million cases of malaria occurring annually. The toll on human life is dire; ranging from 780,000 [2] to a million deaths worldwide [1]. [1]. The deaths occur primarily in young children and pregnant women in developing countries [1]. For children who survive malaria, their mental and physical development is impacted by constant fever and anemia [4]. The threat to pregnant women and their unborn children range from anemia, low birth weight, premature birth and death
Sub saharan countries are the most prevelant for malaria followed by SE Asia. These climates are tropical and sup tropical
which provides the best anti-malarial drugs available and recommended by WHO [6]. The artimisinin in these drugs enhances efficacy and reduces malaria transmission [6]. WHO estimates that in 2010 181 million courses of ACTs was delivered to sub-Saharan Africa up from 158 million courses in 2009 and is recommended as the first-line treatment for malaria from P. falciparum [6]. Another control measure is to distribute long-lasting insecticidal nets (LLIN), which are covered in insecticides and are designed to kill mosquitos. According to WHO, in 2010 145 million nets were delivered to sub-Saharan Africa up from 88.5 million nets in 2009 [6]. This is a huge improvement because it insures that there is preventative access available to poor communities and individuals. It is estimated that 96% of individuals with access to LLIN use the and around 50% of household in sub-Saharan Africa have them [6]. Lastly, the invention and improvement of diagnostic tests has helped immensely; 88 million rapid diagnostic tests were delivered in 2010 up from 45 million in 2008 [6]. Malaria interventions are cost effective as well, ACT costs between $.30- $1.40, LLIN costs $1.39 and lasts three years and rapid diagnostic tests cost $.40 [6].
These are some examples of ACT drugs
Given all the success to these control measures, the downside associated with them has left a gap that needs to be filled. For ACT, the limiting factors are: adopting policies, limited knowledge on safety in pregnancy, and the imbalance between demand and supply [6]. Recently WHO has recommended that a ban be placed on oral artimisinin bases monotherapies due to emergence and spread of drug resistance [6]. 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 [6]. Due to the shortfalls of control measures and continuing prevalence of malaria, the focus has shifted to vaccines as the next major intervention. In a report WHO identified vaccines as a cost effective method to reduce the burden of this disease [7]. The report also identified through cost-effective analysis of existing antimalarial interventions that the economic benefit of reducing or eliminating malaria is enormous [7]. The cost effectiveness of vaccines in public health indicated an economical return in improved health per dollar spent [7].
In theory a blood-stage vaccine would control parasitic infection but not prevent malaria while the transmission blocking vaccines (TBV) or sexual stage vaccine impact the pathogen thus preventing malaria development in mosquitoes but no humans [1]. The most prominent area of research lies in pre-erythrocytic vaccines because there is potential for complete sterilization and immunity[1]. In theory the vaccine would stop parasitic development at the sporozoite stage thus preventing infection in mosquitos and disease in humans [1]. Also, during the pre-erythrocytic stage there is a high-level of sterilizing immunity against heterologous strains of P. falciparum [1].
The majority of the reasearch is done on the p.falciparumAnd focus is on pre-erythrocytic stage
Development of the RTS,S antigenThe surface of the sporozoite contains a surface antigen known as circumsporozoite protein (CS), which was first discovered in the rodent malarial parasite, Plasmodium berghei [1]. This protein is important because it established that the antibodies against it provided protection from malaria [1]. Further research led to the discovery of primate malarial parasite CS protein and of the P. falciparum CS protein [1]. A hybrid vaccine was created which combined an independent T-cell epitope along with the P. falciparum CS protein and hepatitis B surface antigen [1]. This hybrid was called R16HBsAg and it included 16 tandem repeats of the epitope of the P. falciparum CS protein fused with the pre-S2 region of HBsAg [1]. When transformed via Saccharomyces cerevisiae, R16HBsAg assembled into a virus like particle with the CS epitope being exposed to the exterior [1]. When adjuvanted with aluminum salts, R16HBsAg increased antibody response to the CS epitome in mice and rabbits and in clinical trials of R16HBsAg showed that R16HBsAg was safe and immunogenic [1]. All the participants of the trial were given doses at monthly intervals; 20 displayed anti-CS antibody response, 17 displayed antibody titer of ≥ 1200, and 13 with anti- CS antibody response 10 months after vaccination [1]. 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 [1].