Cryptococcus Neophormans Vacine strategy

Workshop #4

Azat Duisembay

Yerbol Nurmaganbetov

We will develop a vaccine about opportunistic bacteria called Cryptococcus Neophormans. Cryptococcus Neophormans (CN) is yeast pathogen that access to organism by respiratory track. If crosses Blood-brain barrier, CN can cause meningitis and encephalitis. As a result patient may die. 

a vaccine formula

Vaccine will consist from Glucuronoxylomannan antigen with adjuvant.

Since patient infected with HIV, they have low level of CD4. We decided to increase number of CD4 cells by injection of genetically engineered CD4 and oral prescription of maraviroc or vicriviroc

mechanism of action,

Since the main problem in AIDS is the enormous decrease in CD4 cell number, we decided to fight against it. It is very hard to amplify and recover the lost CD4 cells, but we still can save the ones that are alive. Then, we rely on their further activation of other immune cells.

HIV recognizes CD4 cells via the CCR5 receptors that are on cells. People lacking those receptors do not acquire AIDS. There are CCR5 co-receptor antagonists that inhibit the interaction of CCR5 receptor of CD4 cell and gp-120 glycoprotein of the HIV. Thus it can avoid fusion of the virus with CD4 [1].

1.     Currently, there are known 4 antagonists. 2 of them are relatively quite trustable. They are maraviroc and vicriviroc. Maraviroc is approved by FDA in 2007. However, vicriviroc is in the III stage of clinical trial now[1]. Using of this drug may lead to higher number of CD4 cells in patient

2.     In addition we can add gene-modified autologous CD4 T cells. CD4 cell genetically modified by Zinc finger nuclease, which targets both CCR5 and CXCR4. As a result CD4 cell do not express both CCR5 and CXCR4.  Clinical trial showed that patient who received altered CD4 cells had stable level of those cells. [3] Modified cell can be specific for CN antigen.

Glucuronoxylomannan is antigen specific for CN [4]. After increasing the number of CD4 cells, it is possible to induce active immunity in the HIV infected individual. Glucuronoxylomannan can be added to adjuvant such as ALUM. ALUM is able to activate DC more efficiently and activate B cell for immunoglobulin production. First of all any antigen presenting cell will engulf antigen with adjuvant, for example DC. Then DC will present antigen on the surface of the MHCII. Then DC will move to secondary lymph node, where will show Antigen to injected CD4 (Th) cells. CD4 cell then will search for specific B cell and activate them. B cell previously identified Antigen by BCR and internalized it. So, B cell now has Antigen on the surface of MHC for T cell recognition. After interaction with CD28, CD40L and different cytokines B cell becomes activated. Consequently, vaccinated patient will obtain memory B cell, which will protect organism from CN. Moreover, thanks to the class switching, it’s expected that anti- Glucuronoxylomannan dimeric IgA will be produced. Dimeric IgA will prevent CN infection in Lung.  

In addition, we believe that Glucuronoxylomannan can activate B cell through T cell independent activation. It is known that T cell independent activation can be induced by polysaccharides and Glucuronoxylomannan is polysaccharide. However, T cell independent activation produce mostly IgM and do not for memory cells. For that reason immunity will be temporal.

Injected CD4 cell can facilitate in formation memory CD8 T cell. CD4 cell will activate naive CD8, it will then change to effector cell and consequently to memory cell.

Antigen proceeded by phagolysosome of DC, degrade to smaller peptides by proteasome. After that, TAP proteins transport peptide to ER. In ER peptides bind to MHC-I. ER transports MHC-I (with peptide) molecule to Golgi complex. Golgi complex transports MHC-I to membrane, where it display it.  DC then present MHC-I to CD8 cell and activate it. After that person will have activated CD8 T cell.

In overall effect, patient will have strong memory B and T cell response against Cryptococcus Neophormans, even if he/she still infected with HIV.

regimen, route of delivery

Vaccine (antigen + adjuvant) will be delivered intravenously once. Maraviroc is taken twice a day orally [2]. Genetically modified CD4 cells will be delivered intravenously for one time.

possible side effects

This solution has its own side effects such as hepatotoxicity or malignancy [1].

References:

[1] Emmelkamp JM, Rockstroh, 2007, JKCCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions--review of the literature. Eur J Med Res. 2007 Oct 15;12(9):409-17. Retrieved on Nov 12, 2015 from http://www.ncbi.nlm.nih.gov/pubmed/17933722

[2] HIGHLIGHTS OF PRESCRIBING INFORMATION, 2007 https://www.viivhealthcare.com/media/32064/us_selzentry.pdf

[3] Bruce et al., Gene transfer in humans using a conditionally replicating lentiviral vector, 2006, retrieved from http://www.pnas.org/content/103/46/17372

[4] Marta et al., Serum Cryptococcal Antigen in Patients with AIDS, 2015, retrieved from from http://cid.oxfordjournals.org/