Advantages and disadvantages of genetically engineered live vaccines

1. Advantages and Disadvantages of
Genetically Engineered
Vaccines
Dr. Bhoj R singh, Principal Scientist (VM)
I/C Epidemiology; Centre for Animal Disease Research and Diagnosis
Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, UP, India.
TeleFax [phone]
Advantage or Disadvantage of
GM Vaccines BR Singh, i/c Epidemiology , CADRAD, IVRI, Izatnagar

2. Vaccinology, a Holy Grail in Medicine.
Genetically Engineered Vaccines/Synthetic
Vaccines/Third Generation Vaccines
“On June 18, 1981, the U.S. government announced the
creation of the world's first genetically engineered
vaccine”. Hepatitis B and Influenza vaccine are also
available. SPF-66 for Malaria, Ty21a for typhoid,
CVD103Hgr for cholera.
‘Inherently unpredictable and possibly dangerous’
The risks are considered to be non-existent, since they
have not been supported by experimental or
epidemiological investigations. But a "Catch-22" situation,
in the sense that such investigations have not been
performed at all.
Advantage or Disadvantage of
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3. GE/ GM vaccines
Live Killed (Non-live)
Live
Define deletion mutant vaccine
Non-defined attenuated strain vaccines
Vectored Vaccine: Transgenic Salmonella, Vaccinia virus etc.
The transgenic plants: edible vaccines viz., transgenic
banana and tomato cure diseases like Cholera, Rrabies and
Hepatitis-B. For FMD transgenic sugar beet.
Killed (Non-live)
Synthetic and recombinant antigen based vaccines
Nano-particle based vaccines
Nucleic acid based vaccines: Plasmid, DNA/ RNA/ PNA/
siRNA based vaccines
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4. Differences between Live and Killed vaccine
Advantage or Disadvantage of
GM Vaccines BR Singh, CADRAD, IVRI, Izatnagar
Criteria Live vaccine Inactivated vaccine
Oral dosing Good immunity No, or poor immunity
Duration of immunity Long Short
Requirement of adjuvant No Yes
Cross protection from related strainsPresent Rare
Safety on inoculation Varies Often safer
Horizontal spread of the vaccine strain Possible Not applicable
Vertical spread of vaccine strainPossible Not possible
Potential contamination Possible Remote chance
Stability and maintenance Poor and difficultGood and easy

5. Advantage or Disadvantage of
GM Vaccines BR Singh, CADRAD, IVRI, Izatnagar
Criteria Live vaccine Inactivated vaccine
CMI induction Good Poor
Secretary IgA and local mucosal immunityGood No
Reversion of vaccine strain to pathogenicPossible No
Persistence in the vaccinee Yes No
Interference from normal flora of vaccineePossible No
Cost of the vaccine Less More
Requirement for immunomodulators No Yes
Vaccine marker Genetic markers Serological markers
Potential for vector vaccine developmentGood Poor
Potential for use in multivalent combinationLess Good
Changes in growth conditions during
production have impact on immunogenicity
Less More

6. Advantages of GE Vaccines
GE Vaccines are either noninfectious or have defined
virulence.
Production can easily be scaled to produce cheap vaccines.
Most vectors are safe, easy to grow and store.
Antigens which do not elicit protective immunity or
which elicit damaging responses can be eliminated from
the vaccine, e.g. Cholera toxin A from cholera vaccine.
Genes for protective antigens of even non-cultivable
viruses/ bacteria/ parasites can used to produce a vaccine.
Chimerical vaccines can be made: Vectored vaccines for
multiple pathogens.
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7. Risk specific to GE vaccines
Genetically engineered bacteria might transfer their new gene
efficiently to indigenous bacteria in gut.
On disintegration GM organisms release their nucleic acids
representing the same unpredictable risk potentials as the DNA and
RNA vaccines.
Naked DNA vaccines on general genetic shuttle vectors, are
constructed to break species barriers but little is known how the GE
vaccine will act in different hosts.
Naked DNA may persist in the environment, upon release or escape to
the wrong place at the wrong time, horizontal gene transfer with
unpredictable long- and short-term biological and ecological effects
are unpredictable.
Consequences are not known of probable random insertions of
vaccine constructs into cellular genomes in target or non-target
species in environment.
-------cont--Advantage or Disadvantage of
GM VaccinesBR Singh, CADRAD, IVRI, Izatnagar

8. Although easy degradation is a serious problem with RNA
vaccine in the lab, RNA may be surprisingly resistant
under natural conditions and RNA recombination is far
more common than DNA recombination, how they will
affect?.
Some environmental pollutants (xenobiotics, i.e. PCBs,
dioxins, heavy metals) may interact with genetically
engineered vaccines, adding to their unpredictability and
the inability to perform meaningful risk assessments .
Recent experiences ought to call for humility with regard
to environmental effects of science and technology. In
many cases, "experts" were proven wrong after damage
had been done. In most of our studies we are able to
estimate only short term effects whereas the long-term
impacts are the most important and serious.
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9. More problems of GE Vaccines
Presence of extraneous agents in live vaccine s while
poor antigenicity of killed vaccines (require adjuvant).
Poor predictability in its behavior.
Problems likely to arise are, identification of
neutralisation antigen, need for proper co and post
translational modifications of viral/ parasitic
polypeptide, need for proper assembly of antigenic
protein to avoid poor immunogenicity, and separation
of recombinant protein from cell constituents.
In bacterial expression systems antigens from viruses
of eukaryotes are not properly expressed due
problems of co translational and post translational
changes.
Advantage or Disadvantage of
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10. Major Problems
Social acceptance
Environmental safety concerns
• Since the genes for the desired antigens must be located, cloned, and
expressed efficiently in the new vector, the cost of production is high.
Biological safety aspects: When engineered vaccinia virus/ Salmonella
are used to vaccinate, care must be taken to spare immunodeficient
individuals.
Potential integration of DNA into host genome leading to insertional
mutagenesis.
Induction of autoimmune responses: anti-DNA antibodies may be
produced against introduced DNA.
Induction of immunologic tolerance: The expression of the antigen in
the host may lead to specific non-responsiveness to that antigen or
eating of too much edible vaccine.
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11. Estimated risks associated with GE Vaccines
Vaccinia virus vectored GE vaccines (VV) found a new
host species i.e, a new reservoir, buffalo.
A recombinant field isolate of capripoxvirus has also been
detected. The new virus was the result of recombination
between a capripoxvirus vaccine strain and a naturally
occurring virus strain.
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12. Questions need to be answered for
acceptance of GE vaccine
Can the vector engage in genetic recombination, or by other means
achieve new genetic material? If so, will the hybrid offspring have
changed their host preferences and virulence characteristics? Changes
in cell, tissue and host tropism? Change in virulence of the carrier
through the incorporation of foreign genes?
Can other microbes present within the ecosystem influence the
infection with the released vaccine strain or its offspring? Can insects
or migrating birds or animals function as vectors for the vaccine strain
its offspring, to disseminate viruses out of their intended release
areas?
For how long can the vaccine strain and its offspring survive outside
host organisms under realistic environmental and climatic
conditions?
Is the vaccine strain and its offspring genetically stable over time?
Reversion to virulence by acquisition of complementation genes
exchange of genetic information with other vaccine or wild-type
strains of the carrier organism and spread of undesired genes such as
antibiotic resistance genes.
Advantage or Disadvantage of
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13. More issues with GE Vaccines
Can the vaccine strain or its offspring establish long-
lasting, clinically mute, persistent or latent infections in
naturally accessible host organisms?
Can the vaccine strain or its offspring activate or aggravate
naturally occurring latent or persistent infections?
Precise function and genetic location of the genes to be
mutated, their genetic stability, potential reversion
mechanisms, possible recombination events with dormant
genes, gene transfer to other organisms as well as gene
acquisition from other organisms by phage transduction,
transposition or plasmid transfer and cis- or trans-
complementation.
Advantage or Disadvantage of
GM Vaccines BR Singh, CADRAD, IVRI, Izatnagar