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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
There are five species of Plasmodium protozoa which infect humans via mosquitos:
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
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
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
Malaria parasite has a complex lifecycle; there are 3 areas of lifecycle development that are the focus of vaccine development research:
Pre-erythrocytic stage
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 antiCS antibody response, 17 displayed antibody titer of 1:1200, and 13 with anti- CS antibody response 10 months after vaccination
R16HBsAg was later redesigned to include T- and Bcell 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
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
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%
RTS,S/AS02A in humans
The results found a higher level of antibodies against the CS protein in
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
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
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
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%
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 1month 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.
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 6 to 12 weeks of age Severe Malaria 36.6% Clinical Malaria 31.3%
47.3%
55.8%
RTS,S/AS01
569/4358 1048/5949
Control Group
293/2179 642/2974
Number of Deaths
Age Group 6-12 weeks 5-17 months RTS,S/AS01 49 56 Control Group 18 28
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
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 anticircumsporozoite antibodies
SPf66 AdCh63/MVA MSP1 PfSPZ MSP3 GMZ2 AMA1-C1/Alhydrogel +CPG 7909 FMP1AS02A
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-RandDstrategy-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., & Crdenas, 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.). . Retrieved from http://www2.keelpno.gr/blog/?p=2178&lang=en
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