Dr. Naveen Thacker *
President IAP 2007 Email: *
New Technologies for Vaccine Development
Several technologies continue to emerge in the field of vaccine development which include advances in molecular biology, immunology, biochemistry and microbiology to further improve the vaccine efficacy, safety, comfort and patient compliance. These modalities and advances are discussed below:

Polysaccharide vaccines are only slightly immunogenic in infants. The solution was to prepare polysaccharide antigens conjugated to a carrier protein. Such complexes are capable of inducing a powerful and durable T-dependent immune response in both adults and children younger than two years of age.

Recombinant Proteins
Pathogens that are grown with difficulty in laboratory, pose problems for the development of vaccines. This is the case for viruses like HBV or HCV, bacteria like Mycobacterium leprae or Helicobacter pylori, and parasites like Plasmodium falciparum . The genes, expressing the antigens, are inserted into a plasmid, which is then introduced into a host cell (by transfection), like a bacterium ( E coli), a yeast ( S. cerevisiae), or mammalian cell culture line (Chinese Hamster Ovary cells, Vero cells). The host cells express the recombinant molecule, which has retained its antigenic and immunogenic properties. Recombinant proteins can be produced in large amounts, are relatively easy to purify and are stable.

Synthetic Peptides
The rationale for synthetic peptide vaccines is to develop a vaccine with a minimal structure, containing a well-identified antigen, in order to induce an effective and specific response, and avoiding potential adverse effects. The advantages of synthetic peptide vaccines are- use without risk of integration within the host genome (as is the case for viral vectors and naked DNA); induction of a well-defined, mono-functional immune response; and a reproducible, large-scale, extremely pure production. Their principal disadvantage is their low immunogenicity.

Viral Vectors
A viral vector is a virus carrying the genes of pathogenic antigens that have been inserted into its own genome. When given to humans, the vectors express the vaccine antigens corresponding to the foreign genes. This technique is very useful for pathogens that are dangerous or technically difficult to handle. The first example of recombinant antigens was in 1982 using a vaccinia vector, member of the family Poxviridae. Other viruses that have been used as vectors include retroviruses , adenovirus, adeno-associated virus and various members of the poxvirus family, such as canarypox and fowl pox.

DNA Vaccines
The gene that codes for the vaccinal antigen is inserted into a DNA plasmid. The DNA plasmid is produced by in E. coli culture, purified and generally injected by the intramuscular route. Once within the cells, the DNA is translated to produce an immunogenic protein. The procedure, called DNA vaccination.
The advantages of DNA vaccines are numerous. They are easier to produce than the "classical" vaccines. They are also very stable and resist extreme temperatures. Consequently, storage, transportation, and distribution are easy and inexpensive.

Newer technologies for Vaccine Delivery
Transcutaneous Immunization

Transcutaneous immunization (TCI) is a novel immunization strategy by which antigen and adjuvant are applied topically to induce potent antibody and cell-mediated immune responses specific to both the antigen and the adjuvant. TCI therefore combines the advantages of needle-free delivery with targeting of the immunologically rich milieu of the skin.
Some of the most promising applications for transcutaneous immunization will be in the delivery of vaccines to prevent epidemics in underdeveloped countries, refugee camps, and chaotic conditions where use of conventional syringe and bottle vaccines may be difficult. There is some promise of combining TI with experimental vaccines for malaria and dengue fever and other infectious diseases that are important target priorities of the World Health Organization.

Bacterial Ghosts
The bacterial ghost system is a novel vaccine delivery system endowed with intrinsic adjuvant properties as well as carrier and targeting functions. Bacterial ghosts are non-living bacterial cells devoid of cytoplasmic contents while maintaining their cellular morphology and native surface antigenic structures including bioadhesive properties. They are produced by PhiZ174 protein E-mediated lysis of Gram-negative bacteria. The retention by ghosts of the morphological characteristics and structural integrity of their living counterparts make them attractive for use as vaccines.

Edible Vaccines
Edible vaccines are prepared by introducing selected genes into plants and inducing the transgenic plant to express the encoded protein by a process called molecular farming. These were conceived and developed by Charles J Arntzen of the Boyce Thompson Institute for Plant Research of Cornel University. The foods under study include bananas, potatoes, tomatoes, lettuce, rice, wheat, soybeans, corn etc. Edible vaccines are in the pipeline against Norwalk virus, entero-toxicogenic E. Coli, V. cholerae, hepatitis B, H. pylori and Rabies virus.

Newer Modalities for Vaccine Administration
Auto Disable Syringes
The reuse of standard single-use disposable syringes and needles places the general public at high risk of disease and death. The AD syringe presents the lowest risk of person-to-person transmission of blood borne pathogens because it cannot be reused. The AD syringe is the equipment of choice for administering vaccines in both routine immunization and mass campaigns.

Monodose Prefilled Injection Devices
Mono dose presentations of vaccines eliminate the risk of cross-contamination and reduce wastage of vaccine. A new plastic pouch-and-needle device, developed by the Program for Appropriate Technology in Health (PATH), USA, with support from the United States Agency for International Development (USAID), is being marketed by BD Inc under the trade name Uniject. This device guarantees the integrity and sterility of the vaccine dose up to the moment of use. It generates 30% less volume and weight of waste than the 2-ml syringe and monodose vial. It possesses the auto-disable property. It occupies less than half the volume of the syringe and vial in distribution. However, the needle-stick hazard remains.

Needle Free Injections
Jet injection is a means of administering vaccines or drugs into, or through the skin without the use of needles. A compression system (mechanical or gas) is used to accelerate drug particles to a relatively high velocity and pressure, allowing them to penetrate the skin and be deposited subcutaneously or into the epidermis. The advantages include usefulness in people who dislike injections like in children and for the administration of multiple injections over a prolonged period of time and it has no risk of needle stick injuries. The disadvantages are the recent reports of spread of hepatitis B due to blood contamination. Types of jet include Multidose jet injectors for mass immunization or Monodose jet injectors for routine immunization.

Combination Vaccines
Combination vaccines make it easy to include new vaccines into routine pediatric vaccination schedules, making them a public health priority . The current recommendation for India, for example, includes vaccinations against six infectious diseases (tuberculosis, diphtheria, tetanus, pertussis, poliomyelitis, and measles) and in some pilot areas hepatitis B too. It would involve 16 different injections in the first 1 to 2 years of life if all injectable vaccine doses were given separately. Combining diphtheria, tetanus and pertussis antigens in a single vaccine (DTP) reduces the number to six injections. The eventual routine administration of currently available vaccines, inactivated polio vaccine (IPV), Hemophilus influenzae type b (Hib), mumps, varicella, and pneumococcal vaccines would make it 11 injections unless many of these new vaccines were given as combinations.

The formulation of new vaccines in which several components are combined in a single injection is complex, because the combination of different antigens must not adversely affect the safety profile of the combination or the immunogenicity of each component. It may also be necessary to show that protective efficacy is retained by the new vaccine for each of its components. Finally, each new component included in a combination vaccine should be immunogenic and safe when administered according to the recommended schedule for routine infant immunization.

There are still many diseases for which we need vaccines - or better vaccines. As advances in fundamental scientific research improves our knowledge of vaccinology, more and more pressure will be put on finding optimal ways of using and distributing these vaccines. The art and politics of immunization is being driven headlong into the 21st century. Progress in both fields will ensure that in the future the world's children will have access to an ever increasing number of safe, effective and acceptable vaccines. Although the challenges are important, the available new technologies, the increasing knowledge on immunology as well as on the pathogen will contribute to the success of new vaccines.
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