Plasmodium falciparum is the most deadly of the malarial species accounting to over 90% of malaria related deaths  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 , with a range of 225  to 300 million cases of malaria occurring annually. The toll on human life is dire; ranging from 780,000  to a million deaths worldwide . . The deaths occur primarily in young children and pregnant women in developing countries . For children who survive malaria, their mental and physical development is impacted by constant fever and anemia . 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 . The artimisinin in these drugs enhances efficacy and reduces malaria transmission . 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 . 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 . 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 . 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 . 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 .
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 . Recently WHO has recommended that a ban be placed on oral artimisinin bases monotherapies due to emergence and spread of drug resistance . 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 . 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 . The report also identified through cost-effective analysis of existing antimalarial interventions that the economic benefit of reducing or eliminating malaria is enormous . The cost effectiveness of vaccines in public health indicated an economical return in improved health per dollar spent .
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 . The most prominent area of research lies in pre-erythrocytic vaccines because there is potential for complete sterilization and immunity. In theory the vaccine would stop parasitic development at the sporozoite stage thus preventing infection in mosquitos and disease in humans . Also, during the pre-erythrocytic stage there is a high-level of sterilizing immunity against heterologous strains of P. falciparum .
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 . This protein is important because it established that the antibodies against it provided protection from malaria . Further research led to the discovery of primate malarial parasite CS protein and of the P. falciparum CS protein . A hybrid vaccine was created which combined an independent T-cell epitope along with the P. falciparum CS protein and hepatitis B surface antigen . 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 . When transformed via Saccharomyces cerevisiae, R16HBsAg assembled into a virus like particle with the CS epitope being exposed to the exterior . 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 . 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 . 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 .
Malaria vaccine presentation
Deluxini Sundralingam Saifuddin Syed
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 protozoawhich infect humans via mosquitos: P. falciparum P. vivax P. malariae P. ovale P. knowelsi
• 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
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
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
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
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
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.
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)
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
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
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%
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
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
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%
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.
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%
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
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 anti–circumsporozoite antibodies
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