Genetically engineered vaccines: An overview

 

-Agnijhar Mandal, West Bengal, India

Despite the early success demonstrated with the hepatitis B vaccine, no other recombinant engineered vaccine has been approved for use in humans. It is unlikely that a recombinant vaccine will be developed to replace an existing licensed human vaccine with a proven record of safety and efficacy. This is due to the economic reality of making vaccines for human use. Genetically engineered subunit vaccines are costlier to manufacture than conventional vaccines, since the antigen must be purified to a higher standard than was demanded of older, conventional vaccines. Each vaccine must also be subjected to extensive testing and review by the FDA, as it would be considered a new product. This is costly to a company in terms of both time and money and is unnecessary if a licensed product is already on the market. Although recombinant subunit vaccines hold great promise, they do present some potential limitations. In addition to being less react genic, recombinant subunit vaccines have a tendency to be less immunogenic than their conventional counterparts. This can be attributed to these vaccines being held to a higher degree of purity than was traditionally done for an earlier generation of licensed subunit vaccines. Ironically, the contaminants often found in conventional subunit vaccines may have aided in the inflammatory process, which is essential for initiating a vigorous immune response. This potential problem may be overcome by employing one of the many new types of adjuvants that are becoming available for use in humans. Recombinant subunit vaccines may also suffer from being too well-defined, because they are composed of a single antigen. In contrast, conventional vaccines contain trace amounts of other antigens that may aid in conferring an immunity to infectious agents that is more solid than could be provided by a monovalent vaccine. This problem can be minimized, where necessary, by creating recombinant vaccines that are composed of multiple antigens from the same pathogen. These issues are less of a concern with a live attenuated vaccine, since these vaccines are less costly, require fewer steps to manufacture, and elicit long-lived immunity after only a single dose. Unfortunately, live vaccines carry a higher risk of vaccine-induced complications in recipients that make their use in highly developed, litigious countries unlikely. In lesser developed countries, where the prevalence of disease and the need for effective vaccines outweighs the risk associated with their administration, live vaccines may play an important role in human health. This review has attempted to make the reader aware of some of the current approaches and issues that are associated with the development of these vaccines. Genetically engineered vaccines hold great promise for the future, but the potential of these vaccines to improve human and animal health has yet to be fully realized.

What Is a Vaccine

A vaccine is any preparation intended to produce immunity to a disease by stimulating the production of antibodies. Vaccines include, for example, suspensions of killed or attenuated microorganisms, or products or derivatives of microorganisms. The most common method of administering vaccines is by injection, but some are given by mouth or nasal spray.

Vaccination Benefits

Vaccination intends to provide individuals with immunological protection before an infection actually takes place. However, the immune system is very complex, and immunity against different infectious agents is based on fine-tuned balances between the various types of cells, signal substances and antibodies that make up the total immune system.

Trends in Vaccine Development

Modern molecular biology, recombinant DNA technology and genetic engineering have opened the road to a number of alternative strategies for vaccine production,

A Genetically Engineered Vaccine Is

A preparation of direct manipulation of genes of weakened or killed pathogen, such as a bacterium or virus that upon administration stimulates antibody production or cellular immunity against the pathogen but is incapable of causing severe infection.

DNA Vaccines

They employ genes encoding proteins of pathogens rather than using the proteins themselves, a live replicating vector, or an attenuated version of the pathogen itself. They consist of a bacterial plasmid with a strong viral promoter, the gene of interest, and a polyadenylation / transcriptional termination sequence. The plasmid is grown in bacteria (e. coli), purified, dissolved in a saline solution, and then simply injected into the host. In present versions only very small amounts of antigens are produced within the vaccinated individual.

Recombinant (DNA) Vaccines

Made by isolation of DNA fragment(s) coding for the immunogenic(s) of an infectious agent/cancer cell, followed by the insertion of the fragment(s) into vector DNA molecules (i.e. plasmids or viruses) which can replicate and conduct protein-expression within bacterial, yeast, insect or mammalian cells. The immunogen(s) may then be completely purified by modern separation techniques. The vaccines tend to give good antibody responses, but weak T-cell activation.

Naked DNA Vaccines

They are engineered from general genetic shuttle vectors and constructed to break species barriers. They may persist much longer in the environment than commonly believed. 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 is a real hazard with such vaccines. There may be harmful effects due to random insertions of vaccine constructs into cellular genomes in target or non-target species.

Live Vector Vaccines

They are produced by the insertion of the DNA fragment(s) coding for an immunogen(s) intended for vaccination into the genome of a no dangerous virus or bacterium, the vector. The insertion is performed in such a way that the vector is still infectious live.

RNA Vaccines

This involves the use of in vitro synthesised RNA (a single-stranded relative of DNA). RNA are different from DNA vaccines in that there is no risk of chromosomal integration of foreign genetic material.

Edible Vaccines

These are produced by making transgenic, edible crop plants as the production and delivery systems for subunit vaccines. Little is known about the consequences of releasing such plants into the environment, but there are examples of transgenic plants that seriously alter their biological environment. A number of unpredicted and unwanted incidents have already taken place with genetically engineered plants.

Making DNA Vaccines

The gene for an antigenic determinant of a pathogenic organism is inserted into a plasmid. This genetically engineered plasmid comprises the DNA vaccine which is then injected into the host. Within the host cells, the foreign gene can be expressed (transcribed and translated) from the plasmid DNA, and if sufficient amounts of the foreign protein are produced, they will elicit an immune response.

GENETIC ENGINEERING A GREAT TOOL IN DEVELOPING NEWER VACCINES

It is possible, using genetic engineering, to introduce a gene coding for an immunogenic protein from one organism into the genome of another (such as vaccinia virus). The organism expressing a foreign gene is called a recombinant. Following injection into the subject, the recombinant organism will replicate and express sufficient amounts of the foreign protein to induce a specific immune response to the protein.

ADVANTAGES OF DNA VACCINES OVER OTHER TYPES OF VACCINES

• Cheaper and easier to produce.

• Safer

• Can elicit antibody and cellular immune responses.

• Stable at a broad range of temperature (no cold-chain requirement).

• Can be designed and produced by genetic engineering to have only the desired antigens or antigenic sequences (epitopes) in the vaccine.

GENETICALLY ENGINEERED VACCINE TRIUMPH OF BIOTECHNOLOGY

The world’s first genetically engineered vaccine against a human disease–Hepatitis B–is considered one of biotechnology’s greatest triumphs. The achievement stands on the shoulders of pioneering work by UW genetics professor Benjamin Hall and then-
postdoctoral researcher Gustav Ammerer to develop genetic engineering techniques using yeast cultures to produce proteins of interest.

HOW HEPATITIS B ENGINEERED VACCINE PRODUCED

Hall and Ammerer fused a segment of viral DNA specifying the surface antigen to the control elements of a yeast gene. When they transferred these hybrid genes into yeast cells, the resulting cultures produced Hepatitis B surface antigen. Serendipitously, these protein building blocks were found to clump together into the immunity-producing overcoat particles. With that observation, the key to a safe and effective vaccine was in hand.

TWO TYPES OF GENETICALLY ENGINEERED VACCINES FOR HUMAN PAPILLOMA VIRUS PREVENTION

• Bivalent human papillomavirus vaccine (HPV2) licensed for use in females

• Either HPV2 or quadrivalent HPV vaccine (HPV4) used for females ages 19-26 years

• Quadrivalent human papillomavirus vaccine (HPV4) licensed for use in males

• HPV4 may be administered to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts.

Gardasil, a genetically engineered vaccine, prevents cervical cancer by blocking infection with the two viruses that together cause about 70 percent of cervical cancers. HPV 16 and 18, both sexually transmitted viruses, are two of the 100-plus types of human papilloma virus.

EMERGING TRENDS IN ENGINEERED VACCINES

Some genetically engineered viral vaccines consist of chimera viruses that combine aspects of two infective viral genomes. One example is the live Flavivirus chimera vaccine against West Nile virus (WNV) in horses (PreveNile), registered in the United States in 2006. The structural genes of the attenuated yellow fever YF-17D backbone virus have been replaced with structural genes of the related WNV. Chimera avian influenza virus vaccines have been produced on a backbone of an existing, attenuated Newcastle disease virus vaccine strain to protection against wild-type influenza virus as well as against Newcastle disease virus.

NEW AND FUTURE VACCINES POSSIBLE NEW DEVELOPMENTS

New prophylactic and therapeutic vaccines will prevent and potentially cure a wide range of diseases by stimulating immune mechanisms. Advances in vaccinology will provide an efficient way to produce long-lasting protective immunity. Vaccines against non-infectious diseases are being trialled and will provide alternative treatments for conditions such as
allergies, cancer, Alzheimer’s, diabetes, other autoimmune conditions and addictions. Advances in DNA Vaccines will allow rapid development of vaccines against potential agents for biological warfare. New delivery technology will provide easier routes of delivery, such as nasal, transcutaneous and oral, without compromising efficacy.

GENETICALLY ENGINEERED VACCINES A FUTURE TOOL

DNA vaccination is a technique for protecting an organism against disease by injecting it with genetically engineered DNA to produce an immunological response. Nucleic acid vaccines are still experimental, and have been applied to a number of viral, bacterial and parasitic models of disease, as well as to several tumour models. DNA vaccines have a number of advantages over conventional vaccines, including the ability to induce a wider range of immune response types.

GENE VACCINES ON TRAILS

Gene vaccines may be relatively new, but they’re the logical outgrowth of two familiar strands of medical science. First is the 200- year-old practice of vaccination, in which the body is infected with a weakened form of a disease that prepares the immune system for a future encounter with the real thing. There are vaccines in the pipeline for bacterial diseases like anthrax, viral pathogens like Ebola, and inheritable diseases, including several forms of cancer and Alzheimer’s. An Alzheimer’s vaccine, for example, would stimulate the immune system to attack the protein deposits in the brain that are caused by the degenerative disorder.

CONCLUSION

The use of new technology, popularly termed “genetic engineering,” has the potential to change radically our approach to making some types of vaccines. At present, acceptance of these new products is slow because of the conservative attitude to releasing genetically modified organisms to the environment. This careful approach should be applauded in the case of recombinants of doubtful pedigree. However, some may continue to be impeded unnecessarily. Scientists can now isolate stretches of DNA constituting individual genes. and analyze their base sequences. Hence deducing the amino acid sequence of their protein products. Pieces of DNA can be trimmed, sorted and multiplied, and removed from the genome of one organism and inserted into the DNA of a heterologous organism. Totally synthetic genes of any DNA base sequence, coding for any peptide or protein, can be made. The manipulation of DNA in this manner is commonly termed “genetic engineering”. Using this technology, it is possible to manipulate the genomes, and hence the phenotypic characteristics of organisms. in novel and exciting ways. In recent years, genetically engineered vaccine strategies have been rushed into common use within such fields as medicine, veterinary medicine and fish farming. Some scientists contend that such vaccines are totally innocuous. But a recent and major research report by Professor Terje Traavik reduces the ‘safe technology’ to sheer naive optimism, and warns in conclusion that ‘many live, genetically engineered vaccines are inherently unpredictable (and) possibly dangerous.’ Changes in attitudes among scientists, medical doctors as well as politicians are badly needed. 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. To the extent that any prior investigations of damaging effects had been undertaken, methods used were inadequate and only capable to reveal short-term effects, whereas the long-term impacts were the most important and serious. There is a most striking lack of holistic and ecological thinking with regard to vaccine risks. This seems to be symptomatic for the real lack of touch between research in medicine and molecular biology on one hand, and potential ecological and environment effects of these activities on the other. In order to make reliable risk assessments, perform sensible risk management with regard to genetic engineering in general, and genetically engineered vaccines in particular, much pertinent knowledge is lacking. The prerequisite for obtaining such knowledge is science and scientists dedicated to relevant projects and research areas. It must be the responsibility of the national governments and international authorities to make funding available for such research. On one hand, this is obviously not the responsibility of producers and manufacturers. On the other hand, risk-associated research must be publicly funded in order to keep it totally independent, which is an absolute necessity for such activities

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