My Scientific Blog - Research and Articles: August 2020

Sunday, August 23, 2020

Symbols of nucleotides and aminoacids

Table 1: Abbreviations (Code) used for nucleotides

IUPAC nucleotide code	Base
A	Adenine
C	Cytosine
G	Guanine
T (or U)	Thymine (or Uracil)
R	A or G
Y	C or T
S	G or C
W	A or T
K	G or T
M	A or C
B	C or G or T
D	A or G or T
H	A or C or T
V	A or C or G
N	any base
. or -	gap

Table 2: Abbreviations (Code) used for amino acids

IUPAC amino acid code	Three letter code	Amino acid
A	Ala	Alanine
C	Cys	Cysteine
D	Asp	Aspartic Acid
E	Glu	Glutamic Acid
F	Phe	Phenylalanine
G	Gly	Glycine
H	His	Histidine
I	Ile	Isoleucine
K	Lys	Lysine
L	Leu	Leucine
M	Met	Methionine
N	Asn	Asparagine
P	Pro	Proline
Q	Gln	Glutamine
R	Arg	Arginine
S	Ser	Serine
T	Thr	Threonine
V	Val	Valine
W	Trp	Tryptophan
Y	Tyr	Tyrosine

Saturday, August 22, 2020

Malaria vaccines under different phases of clinical trial

Table 2: Lists of vaccines under pre-clinical and clinical trials

Phases	Characteristics /Criteria	Examples of Vaccines

Preclinical phase	· Animal models · Choice of relevant animals · Selection of Adjuvants · Immunogenicity studies · Animal Safety studies · Potency assay	· All the vaccines in the clinical trials must be succeed through the preclinical trails

Clinical Phases
Phase Ia	· to provide a preliminary evaluation on safety and immunogenicity of the vaccine candidate · To demonstrate local and systemic reactions (reactogenicity)	· ChAd63/MVA ME-TRAP + · PfXelTOS FMP012 · PfPEBS · ChAd63/MVA PVDBP · Pfs25-VLP · Polyepitope DNA EP 1300
Phase Ib	· To gather information on safety and to observe the immune response after vaccine candidate administration.	· Pfs25-EPA · AMA1-DiCo · P27A · EBA 175.R2 · MSP3-LSP · BK-SE36 · PAMVAC · PRIMVAC · PfPEBS

Phase IIa	· Optimize the vaccine dose · The number of vaccine doses needed to elicit a proper immune · response (antibodies active with regard to clinical endpoints), · The need for an adjuvant and choice of the adjuvant. · The need for booster doses · The administration route: injectable (intramuscular/subcutaneous/ intradermal) or mucosal (oral, intranasal). · The induction of an immune memory and the reactivation kinetics of memory-B cells.	· RTS,S-AS01 ChAd63/MVA ME-TRAP · RTS,S-AS01 fractional dose · GMZ2 · MSP3 [181-276] · Ad35.CS/Ad26.CS · ChAd63/MVA (CS, TRAP, AMA)

Phase IIb	· to evaluate the preliminary efficacy of the vaccine candidate before the initiation of a pivotal phase 3 trial · Adverse effects	· ChAd63/MVA ME-TRAP · PfSPZ · R21/ME-TRAP

Phase III	· To determine the efficacy and safety in target population	· RTS,S-AS01

Pilot Study	· Quality, safety and efficacy · Cost effectivity · Marketing	· RTS,S-AS01

(Source: WHO, Background paper on the RTS,S/AS01 malaria vaccine-2015, Frimpong et al., 2018, Salamanca et al., 2019, Artaud et al., 2019)

Malaria vaccine updates

Table 1: List of malaria vaccines

Type of Vaccines

Name:

Compositions

Beneficial / Limitations

Pre-erythrocytic vaccines

1. RTS,S/AS01E

· Adenovirus (Ad35) vectored circumsporozoite (CS) protein in prime boost with RTS,S/AS01E

· Multiple epitope constructs (ME-TRAP); a pre-erythrocytic fusion antigen consisting of 17 B-cell, CD4+, CD8+ T cell epitopes of 6 Pf antigens fused to the T9/96 allele of TRAP (Thrombospondin related adhesion protein)

· Only the vaccine in Phase 3 clinical trial

· Low efficacy but decreases mortality

2. AdCh63/MVA ME-TRAP

· Simian Adenovirus (Ad35) encoding ME-TRAP boosted with modified vaccinia virus Ankara (MVA)

· Long lasting CD8+ T cell responses

3. Polyepitope DNA EP1300

· DNA vaccine includes multiple epitopes with linker sequences from four pre-erythrocytic antigens CS, SSP2/TRAP, liver stage antigen-1 (LSA-1) and Exported protein-1 (EP-1)

· Immunogenicity is not enhanced in human as compared to animals

4. PfSPZ

· Metabolically active non-replicating malaria sporozoite vaccine (Pf sporozoites prepared by thawing from liquid nitrogen)

· Not protective but need to revised in terms of dose and route of administration

5. Genetically Attenuated sporozoites-GAS

· Safe and immunogenic

6. FP9 CS/MVA CS

· Attenuated fowl pox strain (FP9) expressing CS protein boosted with MVA coding CS protein

· Didn’t boost the T-cell response

7. DNA CS/MVA CS

· Plasmid DNA encoding CS protein replace fowl pox strain (FP9) boosted with MVA coding CS protein

· Modest T-cell response

8. RTS,S/AS02 + MVA CS

· Boosting RTS,S/AS02 with MVA encoding CS

· Greater CMI response

9. CS DNA Immunization or VCL-2510

· Gene for full length CS protein in Plasmid DNA

· No anti-CS antibodies

10. MUST DO5

· Multi-Stage DNA vaccine operation 5 antigens

· 5 antigens; CS, SSP2/TRAP, LSA-1, LSA-3 and EP-1 adjuvanted with GM-CSF (Granulocyte Macrophage colony stimulating factor)

· No efficacy

11. DNA CS / RTS,S/AS02

· DNA vaccine VCL-2510 containing full length CS gene and adjuvanted with RTS,S/AS02

· No significant improvement than using alone

12. RTS,S/AS02 TRAP

· Combination of CS with TRAP

· Improve efficacy

13. HepB Core Ag CS VLP

· Also called ICC-1132 or Malariavax

· Hepatis B core antigen modified to include B-cell and 2 CD4+ epitopes of CS protein

· No efficacy to sporozoites

14. PfCS102

· Chemically synthesized Pf CS protein with C-terminus (Amino acids 282-383)

· Don’t reduce parasitemia

15. FP9/MVA polyprotein

· Prime Boosting with FP9 and MVA viruses with six antigens polyprotein (STARP, TRAP, LSA-1, LSA-3, Pfs16 and EP-1)

· Low efficacy with sporozoite challenge

16. FMP011/AS01B

· LAS-1 E. coli expressed evaluated with AS01B and AS02A

· Associated with acute coronary syndrome

Blood Stage (Erythrocytic) vaccines

1. AdCh63/MVA MSP-1

· Pf Merozoite Surface Protein-1 (MSP-1) expressed and boosted with AdCh63 and MVA vectors

· Low IgG response

2. FMP010/AS01B

· E. coli expressing FVO allele 42kD C terminus of MSP-1 and adjuvants AS01B

· Good immunogenicity but inadequate clinical efficacy

3. FMP2.1/AS02A

· FMP2.1, in which E. coli expressed Apical membrane antigen (AMA-1) and adjuvant AS02A

· Strong Th-2 biased response

4. FMP2.1/AS01B

· FMP2.1, in which E. coli expressed Apical membrane antigen (AMA-1) and adjuvant AS01B

· Adverse effect (rashes after 18 days of vaccination)

5. AMA-C1/Alhydrogel + CPG 7909

· Pichia pastoris expressed Apical membrane antigen (AMA-1) with both FVO and 3D7 strains and adjuvants Alhydrogel + CPG 7909

· Reduction of hemoglobin

6. AdCh63 AMA-1/MVA AMA-1

· Apical membrane antigen-1 (AMA-1) expressed and boosted with AdCh63 and MVA vectors

· CD4+ responses are higher than CD8+ response

7. EBA175RII

· Erythrocyte binding antigen (EBA) in merozoites and highly conserved region of Pf

· Safe and immunogenic

8. SERA5

· Blood stage antigen in trophozoites and schizonts (SE36 expressed in E. coli acts as fragment of SERA5 antigen)

· Safe and 100% seroconversion

9. BSAM-2/Alhydrogel +CPG

· combination vaccine including MSP1 and AMA1 components. It contains a mixture of recombinant proteins with equal parts P. pastoris expressing FVO and 3D7 strains of AMA1 and E. coli expressing the FVO and 3D7 strains of MSP1.

· Under evaluation

10. JAIVAC

· This combination vaccine consists of MSP1 and EBA175, each of which is an E. coli expressed recombinant protein adjuvanted with Montanide ISA 720

· Synergistic effects

11. GMZ2

· L. lactis expressed recombinant fusion protein of glutamate rich protein (GLURP) and MSP-3 adjuvanted with Al(OH)₃

· Acceptable safety

· Both IgG and memory B cell response

12. Combination B (RESA, MSP-1, MSP-2)

13. FMP1/AS02A

14. MSP-1-C1/AlOH/AlOH + CPG

15. MSP2-C1/ISA720

16. AMA1-C1/ISA720

17. AMA-FVO

18. PfCP2.9

· Already terminated (No succeed)

Gametocyte (Transmission Blocking) Vaccines

1. Pfs25

· Ookinete surface protein Pfs25

· The antigen preparations including ookinete surface protein Pfs25, and the gametocyte antigens Pfs48/45 and Pfs230 are used in the TBV vaccines. Pfs25 was the first antigen to progress clinically but the reactogenicity was found to be very low.

· Low reactogenicity

2. Pfs48/45 and Pfs230

· Contain the gametocyte antigens Pfs48/45 and Pfs230

· Low reactogenicity