advantages and disadvantages of genetically engineered live vaccines

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 +91-581-2302188

Advantage or Disadvantage of GM Vaccines BR Singh, i/c Epidemiology , CADRAD, IVRI, Izatnagar

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 GM Vaccines BR Singh, CADRAD, IVRI, Izatnagar

GE/ GM vaccinesLive Killed (Non-live)Live

Define deletion mutant vaccineNon-defined attenuated strain vaccinesVectored 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 vaccinesNano-particle based vaccinesNucleic acid based vaccines: Plasmid, DNA/ RNA/ PNA/ siRNA based vaccines


Differences between Live and Killed vaccine


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 strains Present Rare

Safety on inoculation Varies Often safer

Horizontal spread of the vaccine strain Possible Not applicable

Vertical spread of vaccine strain Possible Not possible

Potential contamination Possible Remote chance

Stability and maintenance Poor and difficult Good and easy


Criteria Live vaccine Inactivated vaccine

CMI induction Good Poor

Secretary IgA and local mucosal immunity Good No

Reversion of vaccine strain to pathogenic Possible No

Persistence in the vaccinee Yes No

Interference from normal flora of vaccinee Possible No

Cost of the vaccine Less More

Requirement for immunomodulators No Yes

Vaccine marker Genetic markers Serological markers

Potential for vector vaccine development Good Poor

Potential for use in multivalent combination Less Good

Changes in growth conditions during

production have impact on immunogenicity

Less More

Advantages of GE VaccinesGE 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.


Risk specific to GE vaccinesGenetically 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--


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.


More problems of GE VaccinesPresence 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.


Major ProblemsSocial acceptanceEnvironmental 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.


Estimated risks associated with GE VaccinesVaccinia 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.


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.


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.


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