Live Attenuated Malaria Vaccine

Tzu-Hao YenJeremy Katusak

Blas Quiroga

What is a Live Attenuated Vaccine?

• A weakened living pathogen that retains all of its antigenic properties, but can no longer cause a pathological condition.

http://www.nature.com/nbt/journal/v25/n3/images/nbt0307-303-F1.gif

Why Live Attenuated Vaccines?• Advantages:

– Mimic natural infection builds up immunity– In comparison to highly purified subunit vaccines,

they are relatively cheap to produce and less sophisticated downstream processes are required

– Most effective type of vaccine

Vaccine ProductionViral Strain

Master Seed

Working Seed

Inoculation

Single Harvest

Purified/Concentrated/Inactivated

Final Bulk + Filling

Final Product

Known Virus Vaccines

Measles Vaccine

Mumps Vaccine

Rubella Vaccine

Oral Polio Vaccine

Chicken Pox Vaccine

Smallpox Vaccine

Article Background

• Plasmodium falciparum sporozoites immunogen (PfSPZ)

• New vaccine• Protected through

hepatic CD8+ cell immunity

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http://www.medicine.mcgill.ca/tropmed/txt/sporozoite-chengmai.jpg

Article Overview

• Live attenuated malaria vaccine– Based on Pf sporozoites– Protected by hepatic CD8+

cells in the liver

Human Study• 80 healthy participants ages 18–50

• Split into four groups• Exposed to several hundred

mosquitoes in a surface area of 56 cm2

• It is near impossible to replicate mosquito bite

http://www.thenakedscientists.com/HTML/uploads/RTEmagicC_the-box.jpg.jpg

Note: SC stands for subcutaneously and ID stands for intradermally

Human Study• Analysis: Blood smears and sera

analysis/assays performed two weeks after each dose to rule out breakthrough infection

• Follow up: Three weeks after final dose, volunteers from groups 1, 2, and 4, as well as 18 nonimmunized control volunteers were exposed to mosquitoes infected with PfSPZ

• Again, analysis was performed

http://img.westmedica.com/vision-at.com/new/big/Vision-Hema_big.png

Primate Study• Rhesus macaques immunized in the

same manner as humans (SC vs IV)

• Exposure was performed through IV inoculation

• This was done to observe likely immune responses

• Assays were performed at 2 weeks and 3 to 4 months after immunizations

http://upload.wikimedia.org/wikipedia/commons/thumb/2/2d/Macaca_mulatta_in_Guiyang.jpg/220px-Macaca_mulatta_in_Guiyang.jpg

Rabbit Study

• New Zealand white rabbits immunized four times at 2-week intervals

• PfSPZ administered in two injections at subscapular (below shoulder blade)region and via IV injection

• Sera analysis performed 2 weeks after the fourth dose

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Mouse Study• Performed to see if IV

administration of irradiated PySPZ could induce high-level protective immunity

• Is this higher than previously evaluated ID and SC administration???

• Exposure performed through IV inoculation and mosquito exposure

• Blood smears were made 7 and 14 days after second exposure (after immunization)

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Results

• Volunteers were immunized by bite of irradiated, PfSPZ infected mosquitos

• Exposed to several hundred mosquitos• Each with <0.5 microliters in infected saliva• Surface area~56cm^2

Results• Some volunteers developed

modest antibody responses to SPZ

• T cell responses were low so doses of asceptic PfSPZ were increased

• 100% in group 4, 9/9 developed T cell responses

• Vaccine was well tolerated and safe

• Determine if protection could be improved by altering route of immunization

Results

• NHP and rabbit studies were conducted for studying further immune responses

• Results were graphed 2 weeks and 3-4 months after vaccination

• None of the animals had positive T cell responses• Revealed there was limited durability in immunity

Results• A-PBMC’s were analyzed for PfSPZ-specific cytokine producing T cells• B-SPICE analysis was used to divide the T cell responses into 7 populations• C-cytokine T-cells individually• D-distribution of PfSPZ-specifics at peak response

Results

Future improvement

• Additional testing is necessary• Available for treating patients• Non-intravenous application of the vaccine• Additional research is also necessary

References• Epstein, J. E., K. Tewari, and K. E. Lyke. "Live Attenuated Malaria Vaccine Designed

to Protect Through Hepatic CD8+ T Cell Immunity." Sciencemag.org. HighWire Press, 28 Oct. 2011. Web. 25 Nov. 2012. <http://www.sciencemag.org.lib-ezproxy.tamu.edu:2048/content/334/6055/475.full.pdf>.

• Epstein, J. E., K. Tewari, and K. E. Lyke. "Supporting Online Material for:Live Attenuated Malaria Vaccine Designed to Protect Through Hepatic CD8+ T Cell Immunity." Sciencemag.org. HighWire Press, 28 Oct. 2011. Web. 25 Nov. 2012. <http://www.sciencemag.org.lib-ezproxy.tamu.edu:2048/content/suppl/2011/09/07/science.1211548.DC1/Epstein.SOM.pdf>.

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