Announcements. Thursday April 19, 2012 : Lecture by Dr. Don Harn on Schistosome vaccines Tuesday April 24, 2012 : Lecture on Vector control Monday April 30, 2012 : Review session Thursday May 3, 2012: FINAL EXAM at Pharmacy School, Room 338: 8-11 AM. CONTROL MEASURES Vaccines and Vectors.
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Vaccines and Vectors
April 17, 2012
Silvia N J Moreno
Control methods should be integrated with the parasite life cycle:
Direct life cycles with no IH (monoxenous): Only the DH and the environments to be considered. For example, safe sewage disposal will give satisfactory control of fecally transmitted monoxenous parasites like Ascaris.
One or more Intermediate hosts (heteroxenous): parasites with an intermediate host often undergo asexual reproduction in the intermediate host. This increase in biotic potential can make control more difficult. For the control of digeneans such as schistosomes, prevention of fecal contamination of snail habitats has to be almost perfect, since a single infected snail can shed thousands of cercariae.
Vector control measures: for the control of parasites
with an arthropod definitive host
Typical transmission cycle of a vector-borne parasite or pathogen between a human host and an arthropod vector, and potential steps for intervention.
Examples of novel control strategies developed based on arthropod genome resources (red shaded text boxes) and the parasite or human host genome resources (yellow text box) are shown. Nature reviews Microbiology 3:262 (2005).
What knowledge is needed to produce a vaccine ?
1. Understand life–cycle of parasite
→ find best target stage.
2. Understand immune mechanisms stimulated by parasite.
→ humoral /cellular response ?
1. Whole pathogens killed prior to inoculation.
2. Attenuated live or low virulence vaccines
3. Protein Subunit vaccines.
→ Natural tissue purified proteins.
→ Recombinant protein antigens.
→ Chemical small peptide vaccines.
4. Nucleic acid vaccines
DNA plasmid vector carry the genetic information for an antigen, which is made inside a host cell and leads to a cell-mediated immune response via the MHC I pathway.
The plasmid DNA vaccine carries the gene for an antigenic pathogen protein.
The plasmid vector is taken up and transcribed in the nucleus. The mRNA is translated into protein.
The protein antigen is degraded by proteosomes into peptides. The derived-peptide binds MHC class I molecules.
Peptide antigen/MHC I complexes are presented on the cell surface, binding cytotoxic CD 8+ lymphocytes, and inducing a cell-mediated immune response.
Some of this protein is released, and it could be bound by antibody molecules on B cells or phagocytosed by macrophages. Protein is digested into small peptides and placed in the binding groove of a cell surface protein MHC II.
The peptides are bound and recognized as foreign by the TCR, the helper T cell releases interleukins (IL) to stimulate both arms of the immune system (humoral and cellular).
(maybe 20,000 proteins in nematodes).
(most research in rodent models)
With a few exceptions protozoal vaccines are live vaccines.
Parasite strains selected for:
Complete but shortened life cycles (Eimeria strains)
Truncated life cycle (Toxoplasma gondii S48 strain which does not form cysts)
Vaccine with inactivated Neospora caninum tachyzoites. Vaccination with Bovilis Neoguard reduces the incidence of abortion due to Neosporosis in cattle
Attenuated virulence by repeated passage through splenectomized calves (Babesia bovis and Babesia bigemina or by in vitro culture (Theileria annulata)
Other kinds of live vaccine are low dose infections and use of chemotherapy to control the infection
Eimeriavax 4m is a live precocious Eimeria vaccine. It is a 4 strain breeder and layer product to prevent coccidiosis reducing the dependence on chemical control of this disease.
Eimeriavax 4m aids in the control of coccidiosis in chickens caused by E. acervulina, E. maxima, E. necatrix and E. tenella.
Eimeriavax 4m was first registered in 2003.
"Livacox" vaccine was also introduced in the late 1980's and comprises attenuated ("precocious") lines except for an egg-adapted line of E. tenella.
This photograph shows the effect of toxoplasmosis on several pairs of twin lambs – one of each pair is relatively normal and the other is smaller and mummified.
For travelers (military) a vaccine holds the greatest promise for protecting them against malaria
Sporozoites are carried through the blood to the liver, invade hepatocytes and undergo asexual (mitotic) replication (exoerythrocytic schizont). After seven days, the liver schizonts rupture to release merozoites into the blood.
Merozoites invades erythrocytes and divides mitotically to form an schizont, containing up to 20 daughter merozoites. These merozoites can re-infect erythrocytes.
A subset of merozoites differentiate into male and female gametocytes, which, when taken up by a feeding mosquito, give rise to gametes. In the mosquito mid-gut, the gametes fuse to form a zygote (ookinete), which penetrates the mid-gut wall and forms an oocyst, within sporozoites develop.
Cell mediated immunity
+/- NK Cells
Transfer antibody to mosquito
Antibody dependent protection
No MHCI or MHCII on RBCs so ADCC (Antibody Dependent cell-mediated cytotoxicty)
+/- Complement Activation
+/- Complement lysis
Vaccine clinical trials are long term studies aimed at assessing the safety, efficacy and immunogenicity of a new vaccine product
Safety, immunogenicity, tolerability, efficacy
Non-immune human volunteers in non-malarious areas.
Safety, immunogenicity, tolerability
Phase IIa: non-immune volunteers
Phase IIb: Immune volunteers
Vaccine efficacy, safety, tolerability, acceptance
Human volunteers. Experimental challenge with infected mosquitos.
Semi-immune residents of malarious areas (all endemicities). Small target population, special groups.
Vaccine efficacy, safety, tolerability, acceptance
Vaccine efficacy, safety, tolerability, acceptance, vaccination strategy, effectiveness
Semi-immune residents of malarious areas.Large target population, whole communities.
A protein particle vaccine in a complex adjuvant
R: central repeat of the csp protein
TS: The entire c-terminus of CS protein (containing known T cell epitopes)
S: hepatitis B virus surface antigen. Several viral antigens, such as the surface and core antigens of HBV, spontaneously form particles, and it has been found to enhance their uptake by antigen-presenting cells, and immunogenicity.
To achieve particle formation co-expression of an excess of non-hybrid HBV S antigen was required to form RTS,S.
Rip Ballou giving himself malaria in 1987. He had been injected with a vaccine candidate a year earlier and he was testing the immunity developed by challenging with malaria parasites.
Schematic representation of RTS,S particles. A, RTS and S proteins;
B, RTS, S particles. HBsAg, Hepatitis B surface antigen (S antigen).