Transcript Why Synthetic Peptide Vaccines?

Vaccines
Leslie Lobel
Department of Microbiology, Immunology & Genetics
Faculty of Health Sciences
Ben Gurion University
E-mail: [email protected]
Phone: 052-6488000
Vaccine Immunobiology
Passive Immunization: Administration of
preformed antibody (hepatitis A, hepatitis B,
measles, rabies, chickenpox, tetanus, botulism,
diptheria
Active Immunization (Vaccination):
prophylactic approach dependent on
specificity and memory
Effective Vaccine Design
Which antigens are likely to induce a useful
protective response?
At what anatomical site is the immune
response required?
Which immunological mechanism(s) is
(are) required for protection?
What adjuvant and immunization schedule
is safe and evokes a protective response?
Practical Considerations
Cost per dose
Biological stability (esp. for live vaccines)
Ease of administration
Benefit versus risk
Adjuvant
A substance that enhances the immune response
to an antigen with which it is mixed
Depot effect
Activation of APC’s and lymphoid cells
Activation of complement
Increased synthesis/activity of cytokines
Carrier
A foreign protein to which nonimmunogenic antigens (eg polysaccharides or
haptens) can be coupled.
This term is also now used to denote a
living organism or vector bearing genes for
expression of foreign antigens
Toxoid
Inactivated toxin which is no longer toxic, but
retains its immunogenicity
Live Vaccines
Able to replicate in the host
Attenuated in pathogencity
Advantages over killed vaccines
May elicit both humoral and cell-mediated
immunity
Generally require fewer doses
Generally result in longer lasting protection
Examples of live vaccines
Viral
Polio, Measles, Mumps, Rubella, Smallpox
(varicella), Chickenpox, Adenovirus (military), Yellow
fever (travelers, military)
Bacterial
Salmonella typhi, Vibrio cholera (travelers),
Tuberculosis (bacille Calmette-Guerin),
Francisella tularensis (tularemia, animal handlers)
Viral Vectors considered for
human vaccines
Poxviruses (vaccinia)
Adenovirus
Adeno-associated virus
Herpes simplex virus
Retrovirus
Alphavirus
Virus-like particles
Killed Vaccines
(whole organisms and subunit).
Unable to replicate in the host
Advantages over live vaccines
Cannot multiply or revert to pathogenicity
Generally less reactogenic
Non-transmissible
Technically more feasible
Examples of killed vaccines
(inactivated whole organisms)
Viral
influenza, rabies, polio, hepatitis A, Japanese, Eastern
and Western encephalitis
Bacterial
Bordetella pertusis (whooping cough), Vibrio cholera
(travelers), Coxiella burnetii (Q fever, animal handlers),
Bacillus anthracis (anthrax, military), Yersinia pestis
(plague, animal handlers)
Examples of subunit vaccines
Viral
Hepatitis B (recombinant surface protein)
Bacterial
Bordetella pertussis (acellular), tetanus (toxoid),
diphtheria (toxoid), anthrax, Salmonella typhi
(conjugate), Hemophilus influenza (conjugate),
Streptococcus pneumonia (conjugate), Neisseria
meningitidis (conjugate)
Vaccine Approaches Under
Development
Synthetic peptides
Delivery of T cell epitopes within
heterologous recombinant polypeptides
Immunomodulation (with cytokines, Mab)
Targeted delivery
Immunization with DNA
Why Synthetic Peptide Vaccines?
 Chemically well defined, selective and safe.
 Stable at ambient temperature.
 Simple and standardized production facility.
Epitopes …
B-cell epitopes
Th-cell epitopes
What Are Epitopes?
Antigenic determinants or Epitopes are the
portions of the antigen molecules which are
responsible for specificity of the antigens in
antigen-antibody (Ag-Ab) reactions and
that combine with the antigen binding site
of Ab, to which they are complementary.
Epitopes could be  contiguous (when Ab binds to a
contiguous sequence of amino acids)
 non-contiguous (when Ab binds to noncontiguous residues, brought together by
folding).
 Sequential epitopes are contiguous
epitopes.
 Conformational epitopes are noncontiguous antigenic determinants.
Retro-Inverso peptides Potential Synthetic peptide Vaccines
• A retro structure is obtained by synthesizing peptides in
reverse order, in which the direction of peptide bond is
reversed and side-chains are oriented in the manner
similar to that in D-enantiomer, which explains why
these two analogs cross-react immunochemically.
• When both of these transformations are combined in
the form of an all-D-retro or Retro-Inverso (RI) peptide,
the side-chains are oriented as in original L-peptide.
• As a result, antibodies raised against the L- or the all-Dretro form cross-react strongly with both structures.
• Ex: RI peptide as vaccine candidate for FMDV (Muller,
S., Brown, F, MHV Van Regenmortel)
Mirror
symmetry
between L- and Dforms of peptides
Note that the retro
modification does not
take
the
peptide
through an axis of
symmetry.
Maternal immunization
Mechanisms by which maternal
antibodies influence infant vaccine
responses: review of hypotheses and
definition of main determinants
Previous hypotheses and their basis

Maternal antibodies inactivate live attenuated vaccines
given to infants.

Maternal antibodies bind vaccine antigen administered
to infants, macrophages dispose of these antigenantibody complexes.

Lower seroconversion rates in presence of higher
compared to lower levels of maternal antibodies

Observed inhibition of infant antibody responses to
killed or subunit vaccines is B cell determinant specific
(but quite variable).
Influence of dose of vaccine on antibody responses to TT in 2week old BALB/c pups
Solid lines: immune mothers
Control mothers
Does this rule out maternal immunization for infant
protection against severe infection during the first
few weeks of life?

Not necessarily, but higher antigenic loads or
more vaccine doses may be necessary for the
infants.
Technology Premise
Identify, Capture and
Produce large quantities
of the most effective human antibodies.
General Introduction - MAbs
• Monoclonal antibody technology, a particular class of
modern biotechnology, can be employed to combat
and prevent viral infections.
• Antibodies are a critical component of the body’s
immune defense against viruses and other infectious
agents.
• Vaccines stimulate the body to produce antibodies that
will recognize a particular virus.
General Intro. – MAbs History
• In the absence of an effective vaccine, monoclonal
antibodies (i.e., fully human or genetically engineered
antibodies) can potentially provide protection from
infection.
• Antibody based therapies have been employed since
their first discovery over a hundred years ago by
Kitasano and Behring.
• The first such therapies used serum from immunized
large animals such as horses and sheep.
General Intro - MAbs Usage Today
• Human and animal serum products are still used today;
however, we now have new tools that allow for the
development of totally human—monoclonal—antibody
based therapeutic drugs.
• There are now 12 monoclonal antibody based
therapeutic products that are approved by the FDA.
• The 12 monoclonal antibody based therapeutic
products are used in a variety of indications, including
cancer, heart disease, arthritis, and infectious
diseases.
Passive Vaccines: Emerging Class
Prophylactic vaccines
Passive vaccines
•
Stimulates immune system to prevent
diseases
Support/replace immune system in curing
diseases
•
Administered either once or a limited
number of times
Are in many cases administered
repeatedly
•
Highly developed regulatory standards
due to significant liability, since
administered to group of healthy people
Regulatory guidelines not yet established,
for most indications, due to significant
fewer potential complications.
•
Low margins in many countries; no
reimbursement by health insurances
Attractive margins, normally covered by
health insurances just as other
therapeutic drugs
Why Not Vaccines?
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Side effects
Compounding effect of multiple vaccinations
Long development time for new indications
Large population that cannot be vaccinated
For biodefense, cannot mass vaccinate against
unknown risk due to the resulting morbidity and
mortality
huMAbs Technologies Evolution –
From Mouse to Human
totally human
fully human
humanized
chimeric
mouse
1970s
1st generation
1980s
2nd generation
1990s
3rd generation
2000s
4th generation