Below is a commentary of mine which I sent to all the principals of the March 25 HIV-1 Vaccine Summit in advance...Fauci, Greene, Gray, Hoxie, Watkins, DAIDS etc. It puts forth some new avenues of HIV-1 Vaccine development worthy of consideration based on my 23 year reading of the literature.

Thanking You In Advance
Jesse Creel
Vaccine Research Advocate
+++++++++++++++++++++++++++++++++++++++++++++++++
HIV-1 Vaccine Summit: Which Direction from Here?

First let me say I wished all success in the HIV-1 Vaccine Summit on
March 25 th, 2008, hosted by DAIDS/NIAID.

Following the failure of the Mrk Ad5 STEP trials (60) HIV-1 Vaccine
development is searching for which path to follow. With your kind
indulgence, below are my thoughts on this.

According to the prevailing opinion on HIV-1 protective immunity, a
successful HIV-1 Vaccine will need to target conserved HIV-1 genome
sequences. The question then arises, how to best target these conserved
HIV-1 sequences?

Several approaches are under consideration currently. At the forefront are
various DNA Prime/Boost vaccine approaches involving the use of a DNA Prime
followed by a recombinant microbial vector boost, e.g., MVA or Adenovirus.
Notably are the delayed PAVE 100 DNA Prime/Adenovirus Boost (1;60) and DNA
Prime/MVA boost (2;60). Another approach uses a DNA Prime
followed by a recombinant protein boost as per ( 3 ; 59) These only being a
sampling of the HIV-1 vaccines under serious development. (9;86)

Given this emphasis on DNA Vaccines, which offers ease of production and low
cost logistical advantages, it seems merited to consider carefully the fact
that no DNA vaccine has shown efficacy in humans despite many years of
research.

One possible reason for the failed efficacy of DNA Vaccines in humans may be
that cellular RNAi mechanisms, as spoken to in abstracts and citations below
(4-8), may target the mRNA of a DNA Vaccine thereby curtailing or preventing
translation into vaccine epitopes/antigens.

On this in email exchanges:

HIV-1 Vaccine Summit Co-chair Warner C. Greene, M.D., Ph.D. Director,
Gladstone Institute of Virology and Immunology replied:

"Micro RNAs, in contrast to synthetic siRNAs, block the translation of mRNAs
into their protein products instead of inducing mRNA degradation. However,
for a vaccine which depends on the production of the antigen, their net
effect is similar. I do not know whether any of the naturally occurring
micro RNAs would be predicted to inhibit production of the protein products
from the current spectrum of DNA vaccines that are being tested. It has
been clear for some time that DNA-based vaccines work significantly less
well in humans than in mice. I suspect the reason for this is
multifactorial and not solely due to micro RNAs."

Bharat Ramratnam, an RNAi researcher at Brown U, said:

"It would entirely depend upon the nucelic acid sequence of the
immunogen--if it were homologous to a miRNA, then a nil to modest to severe
reduction in immunogen transcript level could be expected. We have been
looking at this, but NO conclusive data

Stay tuned...."

Monsef Benkirane, an RNAi researcher and associate editor of the Journal
Retrovirology, said:

"Absolutely, DNA viruses often produce viral miRNA that will either target
viral mRNA or cellular miRNA. I believe that one should try to avoid any
mRNA structure that will serve as substrate for Drosha and Dicer in the
process of making DNA viruses vaccine."

A successful HIV-1 DNA Vaccine will need to target conserved sequences of
HIV-1(10), the very same sequences of mRNA that cellular RNAi will need to
target to curtail HIV-1 replication. Therefore it stands to reason that
cellular RNAi will also target these HIV-1 DNA Vaccine mRNA sequences for
silencing/RNAi thereby curtailing DNA Vaccine Efficacy.

In my humble opinion this is probably the case, and along with other
factors, are the reason DNA vaccines have failed to show efficacy in humans
despite many attempts over a number of years.

Speaking to other factors as to why DNA Vaccines don't show the
efficacy they did in proof of concept small animal trials.

In an email exchange Robert Malone, an early DNA plasmid gene therapy
pioneer, said:

"Basically, the transfection efficiency in larger mammals is not good. If
the original hypothesis of my colleague Dennis Carson held (muscle cells as

APC), then due to absence of costimulatory molecules on muscle cells the
"vaccination" would have evoked tolerance, not immunity! To the extent that
delivery to and expression in muscle is important, it appears to be due to
cross-priming (exosomes?).

Rather, tissue dendritic cells are most likely the important actors."

"I was well aware of the fact that the field "ran off" to prove the utility
in humans of what was really immature technology. The rodent findings were
merely proof of the concept, but the delivery technology was not "enabling"
for larger mammals."

Muscle mass in humans is much greater than in small animals therefore much
of a DNA Vaccine is taken up by muscle cells rather than DCs, as Dr Robert
Malone says above, this would reduce DNA Vaccine efficacy.

Further, according to my understanding, any DNA Vaccine translated peptide
and/or protein mRNA transcript would be processed and presented as antigen
via the endogenous rather than the exogenous/cross-priming HLA I pathway.
The DNA Vaccine construct mRNA transcripts would be treated as mRNA of a
virus which infected the cell. This could result in the killing of some
cells by immune system components, Th1 CTL and Th2 Antibody both I think.


All this doesn't even speak to safety concerns which may result in a delay
in the FDA regulatory approval process for any DNA Vaccine, not covered here
for brevity.

These DNA Vaccine Efficacy and/or Safety problems bring into question the
utility of continued investment of time, effort and money, both public and
private, into a number of HIV-1 DNA Vaccines in clinical trials, spoken to
in an article by Margaret Johnston, head of HIV-1 Vaccines at DAIDS at
NIAID, and Anthony Fauci, head of NIAID . ( 9)

The use of recombinant viral vectors also presents us with several problems.
Pre-existing immunity, as shown in the recent failed Mrk Ad5 vaccine trials
(11;60), is one problem. Anti-vector immune responses would curtail, even
where there is no preexisting immunity, efficacy. These anti-vector immune
responses would also squander immune system components ---cellular and
soluble cytokines such as IL-2 as well as molecular building blocks, e.g., amino
acids, peptides and proteins ---needed for protective immunity. This being
of particular importance in populations under general immunosuppression, as per the case
with the HIV+ and/or HIV- malnourished populations found mainly in the poor
nations, with limited immunologic potential.

Further, these populations are under a high state of immune activation.
(20;65;91;93) Besides endemic gut parasite and other infections, a high state
of immune activation occurs due to multiple insults--- generally squalid
living conditions, unsanitary food, un-potable water, biting insects and
environmental pollution. This highlights the need to use a innocuous vaccine
vector that avoids undue systemic immune activation in order to prevent further
vaccine induced immunosuppressive cytokines such as IL-10 and Tregs which
would reduce vaccine efficacy. (65;92;94-101)

Similar would apply if a systemic adjuvant, as QS-21 adjuvant (Antigenics
Inc., Woburn,MA) (59) was used as part of the vaccine.

Should we be designing vaccines that use microbial vectors, adjuvants or
excess HIV-1 epitopes/antigens that may induce unneeded immune activation,
which may be counterproductive as regards vaccine efficacy by causing
the activation of T Cells unnecessarily?

One consequence of an HIV-1Vaccine that causes undo immune activation
would be, activated T cells are more readily infected by HIV.

Another consequence may be the induction of HIV-1 replication by latently
infected T cells and/or a higher rate of replication by HIV-1 infected T
cells already replicating HIV-1 at lower levels.

Taken together, an HIV-1 vaccine that induces inappropriate activation of
T cells may lead to the higher HIV-1 viral loads characteristic of AIDS
disease progression, while on the other hand it is acting to curtail HIV-1
viral loads, in total, reduced vaccine efficacy.

I think we must choose HIV-1 Vaccine components carefully to insure as
best we can that only cells important to HIV-1 protective immune responses
are activated. This would reduce any possible vaccine induced
contribution to AIDS immune hyper activation pathologies.

Safety issues disfavor viral vaccie vectors. They have been shown to cause
death, Jesse Gelsinger's death caused by an adenovirus vector in gene
therapy trial (12) and disease in some cases, as per OPV actually causing
vaccine induced polio (13;60), MVA causing heart problems(14) and worsened
RSV disease in children upon re-exposure after inactivated RSV vaccination
(60). Of coursethere is also a chance of reversion to virulence upon serial
passage from one person to another over time (15).

Another approach which has fallen out of favor since Dr Donald
Francis/Vaxgen's AIDSVAX, which used only gp120 epitopes from a narrow range
of HIV-1type B strains, failed to show efficacy (16), is the use of Recombinant Peptides in
an HIV-1 vaccine. By expanding the peptide epitopes to be used in a vaccine
tocover multiple conserved consensus HIV-1 sequences from various HIV-1
strains worldwide, this approach deserves further consideration I think.(10)

A HepB Peptide vaccine that has shown efficacy and safety is currently being
used in humans. (17) This should speed FDA approval of a HIV-1 Peptide
Vaccine.

The general concept of a polyvalent peptide prime followed by a
pseudoprotein boost is a viable approach according to my understanding of
the literature over the past 23 years. Recent human Phase I Trials by Dr
Shan Lu, UMASS Medical School, and colleagues, using a polyvalent DNA prime followed by
pseudoprotein boost regimen have shown promise.(3 ; 59) The DNA Prime
epitopes used were from a narrow range of older HIV-1 isolates:

"five plasmids each encoding a codon-optimized gp120 gene sequence from the
following primary HIV-1 envelope proteins: subtypes A (92UG037.8), B
(92US715.6 and Bal), C (96ZM651) and E (93TH976.17) and
the sixth plasmid encoding a codon-optimized gag gene from
subtype C (96ZM651) as previously described [28]."

As regards the pseudoprotein boosters used:

"The recombinant Env protein vaccine components included
in the DP6-001 formulation contain equal amounts of five
gp120 proteins matching that used in DNA prime components
and were produced in CHO cell lines by Advanced BioScience
Laboratories (ABL, Kensington, MD) using GMP compliance as
previously described [28]. The final protein vaccine product
was supplied in saline and re-formulated at the time of injec-
tion with 50_g of QS-21 adjuvant (Antigenics Inc., Woburn,
MA) and 30 mg of excipient cyclodextrin (Cargill Cerestar
USA Inc., Hammond, IN),"

I think a better approach is to use Conserved Immunogenic Consensus
Sequences (ICS) defined by close computer analysis of multiple HIV
clades/strains worldwide, bioinformatics, to point the vaccine induced
immune response to conserved epitopes most likely to offer protection for
all strains of HIV-1 worldwide.(10)

The GAIA HIV-1 Vaccine abstract (10) points out a number of
excellent HIV-1 Conserved Immunogenic Consensus Sequences (ICS) derived from
close computer aided analysis, bioinformatics, of multiple HIV-1 genome
sequences, covering various HIV-1 strains worldwide, which can be used as
HIV-1Epitopes/Antigens in order to conduct comparative studies between DNA and
Peptide/ Pseudoprotein formulations of a HIV-1 Vaccine, using the same ICS
epitopes, to determine which approach is best.

GAIA is a not for profit foundation
(http://www.gaiavaccine.org/matriarch/default.asp)
dedicated to the development of a HIV-1 Vaccine available to rich and poor
alike.

HIV-1's main portals of entry are at various mucosal surfaces and the site
of most CD 4+ T Cell Loss early on. (21-29) It makes good vaccine sense to
target a vaccine to the GALT which can result in good immunity at
various mucosas as well as systemically. (30-34;48-49;85;89) This should
curtail or prevent infection and/or systemic dissemination of HIV-1.

A Gelcap encapsulated (35-37;89)Mannosylated (38-41 ) Self-adjuvanting
(42-47 )Freeze-dried Liposome Vector (36) which targets the GAIA HIV-1
Vaccine components to the mannose receptor on DCs (40;50-52), and DEC-205 on DCs and
B cells (61),can orally deliver both DNA and/or Peptide/Pseudoprotein formulations
of a HIV-1 Vaccine to DCs and B Cells of the GALT.

I suggest we conduct two prong comparative trials using a GAIA HIV-1 ICS
Vaccine Polyvalent Peptide Prime, DNA ICS Prime in one prong and Plain ICS
Peptide Prime in the other prong, and GAIA Recombinant ICS Pseudoprotein
Boost in both prongs to determine which strategy is best.

The presence of DEC-205 on B Cells and DCs is good news. Mannosylated
Liposomes uptake should allow B Cells (53-55 ) and DCs to be used as
APC(55;61).

Mannan-binding lectin (40) should bind the Mannosylated Liposomes vector,
activating the classical complement cascade(62) and inducing
opsonization/phagocytosis and antigen presentation .

Mannosylated Liposome will also provide lipids which are key to proper
trafficking and loading of ICS epitopes onto HLA I & II. (31;43;63)

"Presence of both liposomal lipids and liposomal protein in the trans-Golgi
therefore facilitates the entry of liposomal antigens into the MHC class I
pathway. It is also possible that liposomal lipids are presented to T cells via the
recently described CD1 pathway for lipid antigens. Because
liposome-formulated vaccines have the potential to stimulate antibody as
well as cellular immune responses to protein and lipid components, this
approach could prove to be extremely useful in designing vaccine
strategies."(63)

The use of the CD1 antigen pathway is not spoken to here, however I think it
possible that both MHC I & II and CD1 may be used with this vector strategy.
If so, this would greatly enhance the GAIA HIV-1 ICS Vaccine induced immune
responses.

This delivery of concentrated high dose multiple consensus antigens to GALT
DCs and B cells is crucial in order to evoke mucosal and systemic immune
responses which are very strong in breadth and depth. This is essential
given thesmall number of infectious HIV-1 vs Non-infectious HIV-1(NHIV-1), 1
in 10,000+ HIV-1 progeny(64;66;68 ), essential to protective immunity. We have
a small target of HIV-1 in a large crowd of NHIV-1, therefore we will need
this very strong immune response to insure efficacy. Without infectious HIV-1 capable
of producing both HIV-1 and NHIV-1 there will be no more AIDS.

Both DCs and B Cells have TLR-2 which can bind Mannosylated Liposome
activating DCs and B Cells via the Toll Pathway, adjuvanting actions
akin to LPS/Freud's adjuvant. Causing up-regulation of co-stimulatory
molecules, MHC II and cytokine secretion (55-58;73-82;84) and endocytosis of
the GAIA ICS Liposome Vaccine Vector:

"Thus, antigen linked to the TLR2 ligand can be endocytosed after binding
TLR2, processed via the classical (exogenous) pathway of antigen
presentation, and can enhance the stimulation of T cells. This same route
could be exploited to generate more efficacious vaccines." (70) (71;75)

Multiple pathways of DC and B Cell phagocytosis/uptake of Mannosylated
Liposome encapsulated GAIA ICS antigens should give a stronger vaccine
induced immune response by providing a reciprocal boosting of the DC and B
Cell vaccine induced immune response. (72)

Best would be an oral formulation with no boost required. This would offer
ease of administration, along with several cost and safety advantages when
you consider the need to vaccinate several billion people living mainly in
the resource poor nations with limited healthcare infrastructures and public
transport. This is highlighted by recent reports regarding the reuse of
dirty syringes and medical equipment occurring in the world's richest
nation, the USA. (18) In the resource poor nations this is even more likely
to occur owing to cost considerations as well as lack of education regarding
proper medical hygiene and generally meager healthcare infrastructures, as
per the case of HCV transmission by reusing unsterile syringes in Egypt. (19)

To test this one dose oral vaccination (88-90) possibility I suggest we try,
in addition to the proposed two prong GAIA ICS Prime and Pseudoprotein Boost
above, the administration of peptide and protein components of the vaccine
simultaneously also. This would mimic reasonably well what happens in
natural exposure to HIV-1, where in the majority of exposures no actual
transmission/infection occurs.

Further there is the concern regarding Tregs commonly found in HIV-1/Aids
as indicated by the excellent research of Gene Shearer NCI and colleagues.
(67;69) which could curtail vaccine induced antigen specific CD 4+ T Helper
cells which are crucial to the establishment of long term immunologic memory. The
large number of CD 4+ T Helper cells induced by this GAIA HIV-1 ICS Vaccine
strategy should be able to withstand any ensuing Tregs which tend to come
into play later. (83) Thereby providing a excellent pool of Memory CD 4+ T
Helper (87) able to rapidly respond to future encounters with HIV-1, be it
from further exposures or bouts of HIV-1 replication in vivo in the
chronically HIV-1 +.

In effect, it is hoped that this HIV-1 vaccine strategy will be Therapeutic
and Preventative/Prophylactic!

Thanking you in advance for considering this proposed HIV-1 Vaccine
development strategy.

Jesse Creel
Vaccine Research Advocate
1104 River Valley Dr #3
Flint, MI 48532
Email: JesseCreel@comcast.net

A special thanks to Dr Anne De Groot and colleagues at GAIA Vaccine
Foundation, Dr Gene Shearer at the NCI and Dr Robert Malone for the many
helpful insights and encouragement provided without which I could not have
ever proceeded.

Please see Endnote Regarding Production of GAIA ICS Antigen
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
References
1. PAVE 100
http://www.hivpave.org/about/pave100-copy.html

2. Clin Pharmacol Ther. 2007 Dec;82(6):686-93

3. Springer Semin Immunopathol. 2006 Nov;28(3):255-65

4. Journal of Virology, March 2008, p. 2895-2903, Vol. 82, No. 6

Human Immunodeficiency Virus Type 1 Escape Is Restricted When Conserved
Genome Sequences Are Targeted by RNA Interference

Karin Jasmijn von Eije, Olivier ter Brake, and Ben Berkhout*
Laboratory of Experimental Virology, Department of Medical Microbiology,
Center for Infection and Immunity Amsterdam, Academic Medical Center of the
University of Amsterdam, K3-110, Meibergdreef 15, 1105 AZ Amsterdam, The
Netherlands
Received 14 September 2007/ Accepted 5 December 2007
RNA interference (RNAi) is a cellular mechanism in which small interfering
RNAs (siRNAs) mediate sequence-specific gene silencing by cleaving the
targeted mRNA. RNAi can be used as an antiviral approach to silence the
human immunodeficiency virus type 1 (HIV-1) through stable expression of
short-hairpin RNAs (shRNAs). We previously reported efficient HIV-1
inhibition by an shRNA against the nonessential nef gene but also described
viral escape by mutation or deletion of the nef target sequence. The
objective of this study was to obtain insight in the viral escape routes
when essential and highly conserved sequences are targeted in the Gag,
protease, integrase, and Tat-Rev regions of HIV-1. Target sequences were
analyzed of more than 500 escape viruses that were selected in T cells
expressing individual shRNAs. Viruses acquired single point mutations,
occasionally secondary mutations, but-in contrast to what is observed with
nef-no deletions were detected. Mutations occurred predominantly at target
positions 6, 8, 9, 14, and 15, whereas none were selected at positions 1, 2,
5, 18, and 19. We also analyzed the type of mismatch in the siRNA-target RNA
duplex, and G-U base pairs were frequently selected. These results provide
insight into the sequence requirements for optimal RNAi inhibition. This
knowledge on RNAi escape may guide the design and selection of shRNAs for
the development of an effective RNAi therapy for HIV-1 infections.


* Corresponding author. Mailing address: Laboratory of Experimental
Virology, Department of Medical Microbiology, Center for Infection and
Immunity Amsterdam, Academic Medical Center of the University of Amsterdam,
K3-110, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Phone: 31 20
566 4822. Fax: 31 20 691 6531. E-mail: b.berkhout@amc.uva.nl
Published ahead of print on 12 December 2007.

http://jvi.asm.org/cgi/content/abstract/82/6/2895?etoc

5. Journal of Virology, March 2008, p. 2938-2951, Vol. 82, No. 6

Targets of Small Interfering RNA Restriction during Human Immunodeficiency
Virus Type 1 Replication

Yong Gao,1 Michael A. Lobritz,1,2 Justin Roth,3 Measho Abreha,1 Kenneth N.
Nelson,1 Immaculate Nankya,1,2 Dawn M. Moore-Dudley,1,2 Awet Abraha,1
Stanton L. Gerson,3 and Eric J. Arts1,2*

Division of Infectious Diseases, Department of Medicine,1 Department of
Molecular Biology and Microbiology,2 Case Comprehensive Cancer Center, Case
Western Reserve University, 10900 Euclid Ave., Cleveland, Ohio 441063
Received 26 September 2007/ Accepted 4 January 2008
Small interfering RNAs (siRNAs) have been shown to effectively inhibit human
immunodeficiency virus type 1 (HIV-1) replication in vitro. The mechanism(s)
for this inhibition is poorly understood, as siRNAs may interact with
multiple HIV-1 RNA species during different steps of the retroviral life
cycle. To define susceptible HIV-1 RNA species, siRNAs were first designed
to specifically inhibit two divergent primary HIV-1 isolates via env and gag
gene targets. A self-inactivating lentiviral vector harboring these target
sequences confirmed that siRNA cannot degrade incoming genomic RNA.
Disruption of the incoming core structure by rhesus macaque TRIM5 did,
however, provide siRNA-RNA-induced silencing complex access to HIV-1 genomic
RNA and promoted degradation. In the absence of accelerated core disruption,
only newly transcribed HIV-1 mRNA in the cytoplasm is sensitive to siRNA
degradation. Inhibitors of HIV-1 mRNA nuclear export, such as leptomycin B
and camptothecin, blocked siRNA restriction. All HIV-1 RNA regions and
transcripts found 5' of the target sequence, including multiply spliced
HIV-1 RNA, were degraded by unidirectional 3'-to-5' siRNA amplification and
spreading. In contrast, HIV-1 RNA 3' of the target sequence was not
susceptible to siRNA. Even in the presence of siRNA, full-length HIV-1 RNA
is still encapsidated into newly assembled viruses. These findings suggest
that siRNA can target only a relatively "naked" cytoplasmic HIV-1 RNA
despite the involvement of viral RNA at nearly every step in the retroviral
life cycle. Protection of HIV-1 RNA within the core following virus entry,
during encapsidation/virus assembly, or within the nucleus may reflect virus
evolution in response to siRNA, TRIM5, or other host restriction factors.


* Corresponding author. Mailing address: Division of Infectious Diseases,
BRB 1034, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH
44106. Phone: (216) 368-8904. Fax: (216) 368-2034. E-mail: eja3@case.edu
Published ahead of print on 16 January 2008.

http://jvi.asm.org/cgi/content/abstract/82/6/2938?etoc

6. Nature Medicine 13, 1241 - 1247 (2007)

7. Retrovirology 2005, 2:81doi:10.1186/1742-4690-2-81

8. Nucleic Acids Research, 2007,Vol.35, No. 10 e73

9. N Engl J Med 2007;356:2073-81.


10. Vaccine 23 (2005) 2136-2148

HIV vaccine development by computer assisted design: the GAIA vaccine

Anne S. De Groot a,b,?, Luisa Marconc, Elizabeth A. Bishop a, Daniel Rivera
a, Michele Kutzler d, David B. Weiner d, William Martin b

a TB/HIV Research Laboratory, Brown University, Providence, RI 02912, USA

b EpiVax Inc., Providence, RI 02903, USA

c University of Padva Medical School, USA

d University of Pennsylvania, Philadelphia, PA, USA

Abstract

The design of epitope-driven vaccines that address the global variability of
HIV has been significantly hampered by concerns
about conservation of the vaccine epitopes across clades of HIV. We
developed two computer-driven methods for improving epitope-driven HIV
vaccines: the Epi-Assembler, which derives representative or "immunogenic
consensus sequence" (ICS) epitopes from multiple viral variants, and
VaccineCAD, which reduces junctional immunogenicity when epitopes are
aligned in a
string-of-beads format for insertion in a DNA expression vector. In this
study, we report on 20 ICS HIV-1 peptides. The core 9-mer contained in these
consensus peptides was conserved in 105-2250 individual HIV-1 strains.
Nineteen of the 20 ICS epitopes (95%) evaluated in this study were confirmed
in ELISpot assays using peripheral blood monocytes obtained from 13 healthy
HIV-1 infected subjects. Twenty-five ICS peptides (all 20 of the peptides
evaluated in this study and 5 additional ICS epitopes) were then aligned in
a pseudoprotein string using "VaccineCAD", an epitope alignment tool that
eliminates immunogenicity created by the junctions between the epitopes.
Reordering the construct reduced the immunogenicity of the junctions between
epitopes as measured by EpiMatrix, an epitope mapping algorithm. The
reordered construct was also a more effective immunogen in vivo when tested
in HLA-DR transgenic mice. These data confirm the utility of bioinformatics
tools to design novel vaccines containing "immunogenic consensus sequence"
Tcell epitopes for a globally relevant vaccine against HIV.

Keywords: Epitope; Immunoinformatics; T cell; Major histocompatibility
complex

? Corresponding author. Tel.: +1 401 863 6083; fax: +1 401 863 6087.

E-mail addresses: annied@epivax.com, annied@brown.edu,
anne degroot@brown.edu (A.S. De Groot).

11. Aids Vaccine Advocacy Coalition
Mrk Ad5 HIV-1 Vaccine Trial Failure
http://www.avac.org/ANRS_mtng_summary.htm

12. Nature Medicine 6, 6 (2000) doi:10.1038/71545

13. OPV As Cause of Polio
http://www.polioeradication.org/vaccines.asp

14. MVA and Heart Problems
http://www.bt.cdc.gov/agent/smallpox/vaccination/cardiacrecentvaccinees.asp

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Injections and the Emergence of Epidemic Human Immunodeficiency Virus in
Africa
Preston A. Marx, Phillip G. Alcabes, Ernest Drucker
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of HIV and the AIDS Epidemic (Jun. 29, 2001), pp. 911-920

16. Vaccine has no impact
AIDSVAX's failure a blow to treatment
David R. Baker, SF Chronicle Staff Writer
Thursday, November 13, 2003

17. ENGERIX-B?
[Hepatitis B Vaccine (Recombinant)]
DESCRIPTION
ENGERIX-B [Hepatitis B Vaccine (Recombinant)] is a noninfectious recombinant
peptide vaccine
http://us.gsk.com/products/assets/us_engerixb.pdf

18. CDC Head: Problems at Nevada Clinic Could Be 'Tip of Iceberg'"
Associated Press , (03.04.2008)

19. Dirty needles lead to hepatitis C outbreak - Medical News From Around
The World - Brief Article
Nutrition Health Review, Fall, 2002
EGYPT -- Up to 20 percent of people living in Egypt have tested positive for
hepatitis C, a disease that can cause liver failure, and dirty needles are
thought to be the reason, according to an article in The Lancet (March 11,
2000).
http://findarticles.com/p/articles/mi_m0876/is_2002_Fall/ai_95147890

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human immunodeficiency virus type 1 infection.

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Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human
immunodeficiency virus type 1 infection and substantial delay in restoration
following highly active antiretroviral therapy.

25. J Virol. 2003 Nov;77(21):11708-17.
Antiviral Therapy During Primary SIV Infection Fails to Prevent Acute CD4+
T-cell Loss In Gut Mucosa But Enhances Their Rapid Restoration Through
Central Memory T-cells

26. J Infect Dis. 2008 Feb 8
Persistence of HIV in Gut-Associated Lymphoid Tissue despite Long-Term
Antiretroviral Therapy.

27. J Clin Microbiol. 2008 Feb;46(2):757-8.
Early impairment of gut function and gut flora supporting a role for
alteration of gastrointestinal mucosa in human immunodeficiency virus
pathogenesis.

28. the prn notebook? |volume 12 | www.prn.org
The Gastrointestinal Tract in HIV-1 Infection: Questions, Answers, and More
Questions!
Saurabh Mehandru, MD



29. Journal of Clinical Microbiology, February 2008, p. 757-758, Vol. 46,
No. 2
Early Impairment of Gut Function and Gut Flora Supporting a Role for
Alteration of Gastrointestinal Mucosa in Human Immunodeficiency Virus
Pathogenesis

30. Expert Rev Vaccines. 2007 Apr;6(2):203-12.
Clarification of how HIV-1 DNA and protein immunizations may be better used
to obtain HIV-1-specific mucosal and systemic immunity



31. Eur J Immunol. 2002 Aug;32(8):2274-81.
Systemic immune responses induced by mucosal administration of lipopeptides
without adjuvant

32. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1709-14.
Mucosal immunization with HIV-1 peptide vaccine induces mucosal and systemic
cytotoxic T lymphocytes and protective immunity in mice against intrarectal
recombinant HIV-vaccinia challenge.

33. J Virol. 2004 Jan;78(2):1020-5.
Mucosal and systemic immune responses to a human immunodeficiency virus type
1 epitope induced upon vaginal infection with a recombinant influenza A
virus.

34. Nature Medicine 11, S45 - S53 (2005)
Mucosal immunity and vaccines

35. United States Patent 6726924
Oral liposomal delivery system
US Patent Issued on April 27, 2004
http://www.patentstorm.us/patents/6726924-description.html

36. NanoSorb Gelcaps
Please note towards the end of this slide presentation Nanocaps, dedydrated
liposomes encapsulated in gel caps to protect from degradation in the
stomach and delivery to the gut lumen for release, rehydration and uptake by
DC of GALT
http://www.biopharmasci.com/downloads/nanosorb.ppt

37. BioZone Laboratories Inc Drug Delivery Platforms Available
HyperSorbT - Oral delivery in gel caps of liposomes for improved
bioavailability http://www.biozonelabs.com/html/TechnologyLicensing.htm

38. J Control Release. 2005 Nov 28;108(2-3):484-95. Epub 2005 Sep 19.
The role of dioleoylphosphatidylethanolamine (DOPE) in targeted gene
delivery with mannosylated cationic liposomes via intravenous route.

39. Gene Ther. 2000 Feb;7(4):292-9.
Mannose receptor-mediated gene transfer into macrophages using novel
mannosylated cationic liposomes.

40. Biochim Biophys Acta. 2001 Mar 9;1511(1):134-45.
Involvement of serum mannan binding proteins and mannose receptors in uptake
of mannosylated liposomes by macrophages.

41. J Control Release. 2008 Jan 22;125(2):121-30. Epub 2007 Oct 22.
Efficient targeting to alveolar macrophages by intratracheal administration
of mannosylated liposomes in rats.

42. J Immunol. 2001 Feb 1;166(3):1885-93.
The potent adjuvant activity of archaeosomes correlates to the recruitment
and activation of macrophages and dendritic cells in vivo.

43. Vaccine. 2001 May 14;19(25-26):3509-17.
Immunization of mice with lipopeptide antigens encapsulated in novel
liposomes prepared from the polar lipids of various Archaeobacteria elicits
rapid and prolonged specific protective immunity against infection with the
facultative intracellular pathogen, Listeria monocytogenes.

44. Curr Drug Deliv. 2005 Oct;2(4):407-21.
Archaeosome immunostimulatory vaccine delivery system.
Patel GB, Chen W.

45. Infect Immun. 2000 Jan;68(1):54-63. Links
Archaeosome vaccine adjuvants induce strong humoral, cell-mediated, and
memory responses: comparison to conventional liposomes and alum.

46. J Drug Target. 2003;11(8-10):515-24.
Archaeosomes as self-adjuvanting delivery systems for cancer vaccines.

47. Vaccine. 2007 Dec 12;25(51):8622-36. Epub 2007 Oct 5.
Mucosal and systemic immune responses by intranasal immunization using
archaeal lipid-adjuvanted vaccines.

48. Yakugaku Zasshi. 2007 Feb;127(2):319-26.
[Uniqueness of the mucosal immune system for the development of prospective
mucosal vaccine

49. Med Sci (Paris). 2007 Apr;23(4):371-8.
[Mucosal immunity and vaccine development]
[Article in French]

50. Annu Rev Immunol. 2007;25:381-418.
Mucosal dendritic cells.

51. J Allergy Clin Immunol. 2008
4. Gastrointestinal mucosal immunity

52. Biologicals. 2001 Sep-Dec;29(3-4):183-8.
Chemoselective ligation and antigen vectorization.

53. J Immunol. 2007 Mar 1;178(5):2803-12.
Staphylococcus aureus protein A triggers T cell-independent B cell
proliferation by sensitizing B cells for TLR2 ligands

54. Eur J Immunol. 1994 Oct;24(10):2506-14.
Role of antigen-presenting cells in the polarized development of helper T
cell subsets: evidence for differential cytokine production by Th0 cells in
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55. Eur J Immunol. 2007 Nov;37(11):3040-53.
TLR-mediated stimulation of APC: Distinct cytokine responses of B cells and
dendritic cells.

56. J Exp Med. 2008 Jan 21;205(1):169-81. Epub 2008 Jan 7.
Mannose-binding lectin enhances Toll-like receptors 2 and 6 signaling from
the phagosome.

57. Nature. 1999 Oct 21;401(6755):811-5.
Comment in:
Nature. 1999 Oct 21;401(6755):755-6.
The Toll-like receptor 2 is recruited to macrophage phagosomes and
discriminates between pathogens

58. . Immunobiology Part I. An Introduction to Immunobiology and Innate
Immunity 2. Innate Immunity--Receptors of the innate immune system.
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=toll,pathway&rid=imm.section.193#198


59. Vaccine. 2008 Feb 20;26(8):1098-110. Epub 2008 Jan 10.
Cross-subtype antibody and cellular immune responses induced by a polyvalent
DNA prime-protein boost HIV-1 vaccine in healthy human volunteers.



60. Expert Rev Vaccines. 2008 Mar;7(2):151-3.

Human versus HIV: round 2 defeat in AIDS vaccine development. Lu S. PMID:
18324884



61. Int Immunol. 2006 Jun;18(6):857-69. Epub 2006 Mar 31.
Expression of human DEC-205 (CD205) multilectin receptor on leukocytes.



62. Immunobiology Part I. An Introduction to Immunobiology and Innate
Immunity 2. Innate Immunity
The complement system and innate immunity.

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=mannan%20binding%20lectin&rid=imm.section.161#170

63. Adv Drug Deliv Rev. 2000 Mar 30;41(2):171-88.
Delivery of lipids and liposomal proteins to the cytoplasm and Golgi of
antigen-presenting cells. mangala.rao@na.amedd.army.mil.
Rao M, Alving CR.
Department of Membrane Biochemistry, Bldg. 40, Walter Reed Army Institute of
Research, Washington, DC 20307-5100, USA.

Liposomes have the well-known ability to channel protein and peptide
antigens into the MHC class II pathway of phagocytic antigen-presenting
cells (APCs) and thereby enhance the induction of antibodies and
antigen-specific T cell proliferative responses. Liposomes also serve as an
efficient delivery system for entry of exogenous protein and peptide
antigens into the MHC class I pathway and thus are very efficient inducers
of cytotoxic T cell responses. Soluble antigens that are rendered
particulate by encapsulation in liposomes are localized both in vacuoles and
in the cytoplasm of bone marrow-derived macrophages. Utilizing
fluorophore-labeled proteins encapsulated in liposomes we have addressed the
question of how liposomal antigens enter the MHC class I pathway. After
phagocytosis of the liposomes, the fluorescent liposomal protein and
liposomal lipids enter the cytoplasm where they are processed by the
proteasome complex. The processed liposomal protein is then transported via
the TAP complex into the endoplasmic reticulum and the Golgi complex. Both
the liposomal lipids and the liposomal proteins appear to follow the same
intracellular route and they are processed as a protein-lipid unit. In the
absence of a protein antigen (empty liposomes), there is no
organelle-specific localization of the liposomal lipids. In contrast, when a
protein is encapsulated in these liposomes, the distribution of the
liposomal lipids is dramatically affected and the liposomal lipids localize
to the trans-Golgi area. Localization of the protein in the trans-Golgi area
requires liposomal lipids. Similarly, for the localization of liposomal
lipids in the trans-Golgi area, there is an obligatory requirement for
protein. Therefore, the intracellular trafficking patterns of liposomal
lipids and liposomal protein are reciprocally regulated. Presence of both
liposomal lipids and liposomal protein in the trans-Golgi therefore
facilitates the entry of liposomal antigens into the MHC class I pathway. It
is also possible that liposomal lipids are presented to T cells via the
recently described CD1 pathway for lipid antigens. Because
liposome-formulated vaccines have the potential to stimulate antibody as
well as cellular immune responses to protein and lipid components, this
approach could prove to be extremely useful in designing vaccine strategies.

PMID: 10699313 [PubMed - indexed for MEDLINE]


Related Links
a.. Trafficking of liposomal antigen to the trans-Golgi of murine
macrophages requires both liposomal lipid and liposomal protein. [Exp Cell
Res. 1999]
b.. Visualization of peptides derived from liposome-encapsulated proteins
in the trans-Golgi area of macrophages. [Immunol Lett. 1997]
c.. Liposomes containing lipid A serve as an adjuvant for induction of
antibody and cytotoxic T-cell responses against RTS,S malaria antigen.
[Infect Immun. 1998]
d.. Human dendritic cells and macrophages exhibit different intracellular
processing pathways for soluble and liposome-encapsulated antigens.
[Immunobiology. 2005]
e.. Cytotoxic T lymphocytes induced by liposomal antigens: mechanisms of
immunological presentation. [AIDS Res Hum Retroviruses. 1994]

All Related Articles Link:



http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=pubmed_pubmed&LinkReadableName=Related%20Articles&IdsFromResult=10699313&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA



64. Program Abstr Conf Retrovir Oppor Infect 11th 2004 San Franc Calif. 2004
Feb 8-11; 11: abstract no. 450.
CD4+ T-cell Depletion in AIDS: Synergy between Non-infectious HIV-1 and
Other Viruses Induces Selective Apoptosis via a TRAIL/TRAIL
Receptor-dependent Mechanism

65. Clin Immunol. 2008 Mar;126(3):235-42. Epub 2007 Oct 3. Chronic innate
immune activation as a cause of HIV-1 immunopathogenesis.

66. Clin Immunol. 2007 May;123(2):121-8. Epub 2006 Nov 16. HIV-1
immunopathogenesis: how good interferon turns bad.

67. Blood. 2006 Dec 1;108(12):3808-17. Epub 2006 Aug 10. HIV-1-driven
regulatory T-cell accumulation in lymphoid tissues is associated with
disease progression in HIV/AIDS.

68. Blood. 2005 Nov 15;106(10):3524-31. Epub 2005 Jul 26. CD4+ T-cell death
induced by infectious and noninfectious HIV-1: role of type 1
interferon-dependent, TRAIL/DR5-mediated apoptosis.

69. J Immunol. 2005 Mar 15;174(6):3143-7. The prevalence of regulatory T
cells in lymphoid tissue is correlated with viral load in HIV-infected
patients.

70. Eurekah Bioscience Collection Signal Transduction The Function of
Toll-Like Receptors--TLR Ligand Linked Antigen Presentation in Immature DCs

Human immature DCs derived from bone marrow, pulsed with antagonistic TLR2
specific mAbs containing ? light chains, could stimulate a C? specific CD4+
T cell clone in the absence of maturation effects on iDCs (Fig. 7C). An
isotype/light-chain matched control antibody produced a two to three orders
of magnitude lower response, indicating enhanced antigen presentation via
TLR2. Stimulation was TLR2 specific, as antibodies against other surface
molecules such as CD62 and CXCR1 were not stimulatory. Inhibitors of
lysosomal degradation, processing and MHC class II presentation like
chloroquine, leupeptin or brefeldin A almost completely abolished T cell
stimulation. Furthermore, an anti-TLR2 mAb was directly shown to reside in
endosomal vesicles in pulsed iDCs. 31 Thus, antigen linked to the TLR2
ligand can be endocytosed after binding TLR2, processed via the classical
(exogenous) pathway of antigen presentation, and can enhance the stimulation
of T cells. This same route could be exploited to generate more efficacious
vaccines.

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=tlr,maturation,antibody&rid=eurekah.section.26308

71.J Biol Chem. 2007 Jul 20;282(29):21145-59. Epub 2007 Apr 26. Distinct
uptake mechanisms but similar intracellular processing of two different
toll-like receptor ligand-peptide conjugates in dendritic cells.

72. Blood. 2006 Jul 15;108(2):544-50. Epub 2006 Mar 14. Synergistic
activation of dendritic cells by combined Toll-like receptor ligation
induces superior CTL responses in vivo.

73. J Immunol. 2004 Apr 15;172(8):4733-43. A Toll-like receptor 2 ligand
stimulates Th2 responses in vivo, via induction of extracellular
signal-regulated kinase mitogen-activated protein kinase and c-Fos in
dendritic cells.

74. J Virol. 2003 Oct;77(19):10250-9. Yeast-derived human immunodeficiency
virus type 1 p55(gag) virus-like particles activate dendritic cells (DCs)
and induce perforin expression in Gag-specific CD8(+) T cells by
cross-presentation of DCs.

75. J Immunol. 2003 Jul 1;171(1):32-6.

Cutting edge: link between innate and adaptive immunity: Toll-like receptor
2 internalizes antigen for presentation to CD4+ T cells and could be an
efficient vaccine target.Schjetne KW, Thompson KM, Nilsen N, Flo TH,
Fleckenstein B, Iversen JG, Espevik T, Bogen B.

Institute of Immunology, University of Oslo, Rikshospitalet, Oslo, Norway.
k.w.schjetne@labmed.uio.no

An ideal vaccine for induction of CD4(+) T cell responses should induce
local inflammation, maturation of APC, and peptide loading of MHC class II
molecules. Ligation of Toll-like receptor (TLR) 2 provides the first two of
these three criteria. We have studied whether targeting of TLR2 results in
loading of MHC class II molecules and enhancement of CD4(+) T cell
responses. To dissociate MHC class II presentation from APC maturation, we
have used an antagonistic, mouse anti-human TLR2 mAb (TL2.1) as ligand and
measured proliferation of a mouse Ckappa-specific human CD4(+) T cell clone.
TL2.1 mAb was 100-1000 times more efficiently presented by APC compared with
isotype-matched control mAb. Moreover, TL2.1 mAb was internalized into
endosomes and processed by the conventional MHC class II pathway. This novel
function of TLR2 represents a link between innate and adaptive immunity and
indicates that TLR2 could be a promising target for vaccines

76. J Immunol. 2004 Sep 15;173(6):3916-24. Microglia initiate central
nervous system innate and adaptive immune responses through multiple TLRs

77. Nippon Ishinkin Gakkai Zasshi. 2002;43(3):133-6. Receptor-mediated
recognition of Cryptococcus neoformans.

78. Curr Mol Med. 2005 Jun;5(4):413-20. The cellular responses induced by
the capsular polysaccharide of Cryptococcus neoformans differ depending on
the presence or absence of specific protective antibodies.Vecchiarelli A.

79. J Immunol. 2001 Sep 15;167(6):3316-23. Predominant role of toll-like
receptor 2 versus 4 in Chlamydia pneumoniae-induced activation of dendritic
cells.

80, J Immunol. 2003 Aug 1;171(3):1441-6. Heat-killed Brucella abortus
induces TNF and IL-12p40 by distinct MyD88-dependent pathways: TNF, unlike
IL-12p40 secretion, is Toll-like receptor 2 dependent.

81. Nat Immunol. 2000 Dec;1(6):502-9. OmpA targets dendritic cells, induces
their maturation and delivers antigen into the MHC class I presentation
pathway

82. J Clin Invest. 2005 Nov;115(11):3265-75. Epub 2005 Oct 13. Endocytosis
of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral
RNA interactions.

83. The Journal of Immunology, 2008, 180: 1405-1413. Suppression of Mature
Dendritic Cell Function by Regulatory T Cells In Vivo Is Abrogated by CD40
Licensing1

84. Mucosal Immunology (2008) 1, 156-168 The contribution of PARs to
inflammation and immunity to fungi

http://www.nature.com/mi/journal/v1/n2/full/mi200713a.html

85. Yakugaku Zasshi. 2007 Feb;127(2):319-26.
[Uniqueness of the mucosal immune system for the development of prospective
mucosal vaccine]

86. The Maturing Immune System: Implications for Development and Testing
HIV-1 Vaccines for Children and Adolescents

http://www.medscape.com/viewarticle/524225_print

87. J Immunol. 2004 May 1;172(9):5240-8. Antigen-specific T cell repertoire
modification of CD4+CD25+ regulatory T cells.

88. Expert Opin Drug Deliv. 2007 Jul;4(4):323-40. Oral vaccination: where we
are?

89. Methods. 2006 Feb;38(2):150-7. Mucosal immunization using recombinant
plant-based oral vaccines.

90. Immunol Cell Biol. 2005 Jun;83(3):257-62. Oral hepatitis B vaccine
candidates produced and delivered in plant material.

91. AIDS 1998, 12: 2387-2396 Immune activation in HIV-infected African
individuals

92. J. Exp. Med., Volume 188, Number 12, December 21, 1998 2205-2213 Viral
Immune Evasion Due to Persistence of Activated T Cells Without Effector
Function

93. The Journal of Infectious Diseases 1999; 179: 859 -870 Shorter Survival
in Advanced Human Immunodeficiency Virus Type 1 Infection Is More Closely
Associated with T Lymphocyte Activation than with Plasma Virus Burden or
Virus Chemokine Coreceptor Usage

94. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4345-54. A unique subset of
CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth
factor-beta1 mediates suppression in the tumor microenvironment.

95. Clin Vaccine Immunol. 2007 Sep;14(9):1127-37. Epub 2007 Jul 18.
Dendritic cell function during chronic hepatitis C virus and human
immunodeficiency virus type 1 infection.

96.Eur J Immunol. 2007 Jul;37(7):1887-904. Impairment of dendritic cell
function by excretory-secretory products: a potential mechanism for
nematode-induced immunosuppression.

97. Nature Dec 5;420:502-507. Belkaid Y, Piccirillo CA, Mendez S, Shevach
EM, Sacks DL. CD4+CD25+regulatory T cells control Leishmania major
persistence and immunity.

98. Current Opinion in Immunology Published online 2/7/04 Development and
function of CD25+CD4+ regulatory T cells

99. Current Opinion in Immunology Published online 2/11/04 Immunoregulatory
T cells in tumor immunity

100. Cancer Res. 2003 Aug 1;63(15):4516-20. Human CD4(+) CD25(+) Regulatory
T Cells Suppress NKT Cell Functions.

101. J Virol. 2002 Aug;76(15):7528-34. Selective loss of innate CD4(+) V
alpha 24 natural killer T cells in human immunodeficiency virus infection.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

Endnote Regarding Production of GAIA ICS Antigen

GMP Production of GAIA ICS cell-derived Peptide and Peusdoprotien antigen
for R & D and clinical trials. Followed up with full scale production in
transgenic plants should result in high yield, low cost, high quality and
stable for many years at room temperatures GAIA ICS Peptide and
Peusdoprotein antigen to be used in a Global HIV-1 Vaccination Campaign.



J Drug Target. 2003;11(8-10):539-45. Advantageous features of plant-based
systems for the development of HIV vaccines.

Journal of the American College of Nutrition, Vol. 21, No. 90003, 212S-217S
(2002) Foods as Production and Delivery Vehicles for Human Vaccines

Influenza and Other Respiratory Viruses, Volume 1, Number 1, January 2007 ,
pp. 19-25(7) A launch vector for the production of vaccine antigens in
plants

Methods. 2006 Feb;38(2):150-7. Mucosal immunization using recombinant
plant-based oral vaccines.

Immunol Cell Biol. 2005 Jun;83(3):257-62. Oral hepatitis B vaccine
candidates produced and delivered in plant material.

Expert Opin Drug Deliv. 2005 Jul;2(4):719-28. Delivery of plant-derived
vaccines.

Int J Parasitol. 2003 May;33(5-6):479-93. Plant-based vaccines.

Vaccine Volume 24, Issue 5 , 30 January 2006, Pages 691-695 Oral
immunogenicity of a plant-made, subunit, tuberculosis vaccine

J Biotechnol. 2005 Oct 17;120(1):121-34. Epub 2005 Jul 18. Plants as
bioreactors: a comparative study suggests that Medicago truncatula is a
promising production system.

Transgenic Res. 2007 Jun;16(3):315-32. Epub 2007 Apr 14.Production of
vaccines and therapeutic antibodies for veterinary applications in
transgenic plants: an overview.

Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6864-9. Epub 2007 Apr 11.
Smallpox subunit vaccine produced in Planta confers protection in mice.

Ann N Y Acad Sci. 2007 Apr;1102:121-34. Bioproduction of therapeutic
proteins in the 21st century and the role of plants and plant cells as
production platforms.

BMC Biotechnol. 2007 Feb 26;7:12. Expression, intracellular targeting and
purification of HIV Nef variants in tobacco cells.

J Biotechnol. 2007 Feb 20;128(3):512-8. Epub 2006 Nov 16. Multimerization of
peptide antigens for production of stable immunogens in transgenic plants.

Expert Rev Vaccines. 2006 Apr;5(2):249-60. Plant-derived vaccines: a look
back at the highlights and a view to the challenges on the road
ahead.Thanavala Y, Huang Z, Mason HS.

Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263,
USA. yasmin.thanavala@roswellpark.org

The sobering reality is that each year, 33 million children remain
unvaccinated for vaccine-preventable diseases. Universal childhood
vaccination would have profound effects on leveling the health inequities in
many parts of the world. As an alternative to administration of vaccines by
needle and syringe, oral vaccines offer significant logistical advantages,
as the polio eradication campaign has demonstrated. Over the past decade,
the expression of subunit vaccine antigens in plants has emerged as a
convenient, safe and potentially economical platform technology, with the
potential to provide a novel biotechnological solution to vaccine production
and delivery. As this technology has come of age, many improvements have
been made on several fronts, as a growing number of research groups
worldwide have extensively investigated plants as factories for vaccine
production. This review attempts to highlight some of the achievements over
the past 15 years, identify some of the potential problems and discuss the
promises that this technology could fulfill. PMID: 16608424

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