Submitted to Dr.

Sadaf Zaidi
Submitted by Mehak Toor
Dated 17 Dec 2012

MALARIAL VACCINE DESIGN USING

NANOPARTICLES

Nanoparticles for vaccine development

The geometry of the nanoparticle and its resemblance to small viruses, will trigger a strong
immune response based on repetitive antigen display - a concept that now is increasingly
exploited for producing novel vaccines that yield high titers of specific antibodies by using viruslike-particles as repetitive antigen display systems. Such de novo designed nanoparticles
eliminates the need for virus-based designs, and allow for high flexibility in vaccine design.
Epitopes of any pathogen can readily be engineered onto the surface of the nanoparticle, thus
allowing for the easy generation of a whole variety of different vaccines.
Synthetic vaccine candidates can now be developed against several major human pathogens.
Immunogenic peptide sequences characteristic for these pathogens will be displayed on the
surface of a peptide nanoparticle. In addition to its ability to elicits high titer of serospecific
neutralizing antibodies, the particulate structure will guide the nanoparticles to antigen
presenting cells and induce CD4 proliferative responses and cytotoxic T lymphocytes, thus
inducing long-term immunologic memory.

Malarial epitope as an immunogen

Designing nanoparticles presenting the epitopes of any of the major Plasmodium falciparum
protein antigens causing malaria (e.g. from the MSP-1, the AMA-1, the CS proteins, etc.)
repetitively and rigidly on their surface is possible. Using the same approach, synthetic subunit
vaccines can also easily be designed against any other pathogens. Especially enveloped viruses
represent an ideal target as their surface proteins are characterized by trimeric coiled-coil
proteins, which are also building blocks of our nanoparticles.
This is a design and production of a prototypic malaria vaccine based on a highly versatile selfassembling polypeptide nanoparticle (SAPN) platform that can repetitively display antigenic
epitopes. This platform has been used to display a tandem repeat of the B cell immunodominant
repeat epitope (DPPPPNPN)(2)D of the malaria parasite Plasmodium berghei circumsporozoite
protein. Administered in saline, without the need for a heterologous adjuvant, the SAPN
construct P4c-Mal conferred a long-lived, protective immune response to mice with a broad
range of genetically distinct immune backgrounds including the H-2(b), H-2(d), and H-2(k)
alleles. Immunized mice produced a CD4(+) T cell-dependent, high-titer, long-lasting, highavidity Ab response against the B cell epitope. Mice were protected against an initial challenge
of parasites up to 6 mo after the last immunization or for up to 15 mo against a second challenge
after an initial challenge of parasites had successfully been cleared. Furthermore, we demonstrate
that the SAPN platform not only functions to deliver an ordered repetitive array of B cell peptide
epitopes but operates as a classical immunological carrier to provide cognate help to the P4cMal-specific B cells.

Structure of nanoparticle to which the epitope will be attached

For vaccine development it is very important that the structure of viral epitope is similar to the
naturally occurring viral protein. The tandem repeat of the B cell immunodominant repeat
epitope (DPPPPNPN)(2)D of the malaria parasite Plasmodium berghei circumsporozoite protein
antigen has an -helical trimeric coiled-coil structure. So, the nanoparticles as designed by
Raman et al. can be utilized for displaying the suggested antigen. Raman et al. described the
design and production of a peptide that selfassembles into a predicted regular icosahedral
nanoparticle of about 16 nm of diameter. The monomeric peptide building block of the
nanoparticle consists of a modified pentameric coiledcoil from the cartilage oligomerization
matrix protein (COMP) and a de novo designed trimeric. The trimeric coiled-coil if extended by
the sequence of the suggested epitope would act as the antigen displayed and they would cause
the production of antibodies by immune system.

References
Kaba et al., 2009: Kaba SA, Brando C, Guo Q, Mittelholzer C, Raman S, Tropel D, Aebi U,
Burkhard P, Lanar DE. A nonadjuvanted polypeptide nanoparticle vaccine confers long-lasting
protection against rodent malaria. Journal of immunology (Baltimore, Md. : 1950). 2009;
183(11); 7268-7277.
Brian Tripeta, Daniel J. Kaoa, Scott A. Jeffersb, Kathryn V. Holmesb, Robert S. Hodges,
Template-based coiled-coil antigens elicit neutralizing antibodies to the SARS-coronavirus
(2006) Journal of Structural Biology Volume 155, Issue 2, August, Pages 176194
Senthilkumar Raman, Gia Machaidze, Ariel Lustig, Ueli Aebi, Peter Burkhard, Structure-based
design of peptides that self-assemble into regular polyhedral nanoparticles Nanomedicine:
Nanotechnology, Biology and Medicine Volume 2, Issue 2, June 2006, Pages 95102