Dr. Wahied Khawar Balwan
A Human Vaccine is a formulation that contains substances that have features which match materials in part or in whole to pathogens (disease causing microorganisms) against which bodily protection is sought. Infection is caused to human when pathogenic microbes invade the body. Human body has lymphocytes or white blood cells to protect from pathogens. Human body protects itself from the attacks of invading pathogens by innate as well as acquired immune responses. Protective immunity is acquired by the body through vaccination. In these processes mainly four kinds of white blood cells get directly involved which include the T-cells, B-cells, the other lymphocytes and the macrophages. On vaccination, certain lymphocytes engulf the antigenic part from the vaccine substance, process it and present it to the resting T cells, which are of various kinds. Dendritic cells, which are monocytes and are a part of white blood cells, also assist in the presentation of antigens to the lymphocytes. On presentation of the antigens, the resting immune cells effect the formation of the effector T and Bcells as well as memory T and B cells. The effector cells act immediately on the pathogens after their formation while the memory cells protect the vaccinated individuals during future infection. The molecular mechanism of acquiring immunity through vaccination is indeed complex.
In brief, the resting marker T cells designated as CD4+ T Helper cell differntiate into several lineages after vaccination, distinct among these are CD4+ T Helper-l , CD4+ T Helper-2, CD4+ T Helper-17 and CD8+ T cells. Each linage of these T cells plays a role in the protection process. The T-cell mediated rationalization encompasses induction of CD4+ and/or CD8+ T cells of enough magnitude, producing the phenotypes that have high effector properties and contribute directly to clearance of pathogens via cell-mediate effector mechanisms. In another route, the T helper cells designated as CD4+ T Helper-2 activate the B cells to produce B effector cells which are capable of producing clonal immunoglobulins that have the capacity to bind to the pathogens or to the toxins secreted by them. The complex formed by the interaction of the clonal immunoglobulins and the pathogen or itsparts including the toxins are recognized and engulfed by the macrophages and removed from the body continuously, thereby protecting the vaccinated individuals. In vaccination process, production of clonal immunoglobulins with the aim of neutralizing the pathogens or their parts is the main aim and is an easily measurable parameter for developing corelationships between and among multiple parameters of vaccine components and effectiveness of protection of the vaccinated individuals. The T-cell mediated induction of CD4+ and/or CD8+ T cells for producing the phenotypes with high effector properties of clearing of pathogens is an emerging area in vaccination.
All the vaccines approved for human use are safe as these are rigorously tested for safety and efficacy before licensing approvals are accorded for human use.
Presently there are at least twenty six vaccines, each to prevent infection from one individual pathogen. These are used worldwide to protect human from multiple infections. These diseases include vaccines for viral diseases namely dengue fever, hepatitis-A, hepatitis-B, herpes zoster, influenza, Japanese encephalitis, measles, mumps, papilloma virus (human), polio, rabies, rotavirus, rubella, small pox, vericella virus (chicken pox) , yellow fever and Covid-19; and bacterial diseases such as anthrax; cholera; diphtheria; haemophilus influenzae type b; meningococcal vaccine type B, multivalent vaccine, meningococcal poly saccharide vaccine as well as meningococcal conjugate vaccine; pertussis (whooping cough); tetanus; tuberculosis and typhoid fever.
Vaccines are either live-attenuated microbes or inactivated pathogens or antigens selected from portions of pathogenic microbial metabolites. Antigens which are selected from portions of pathogenic microbial metabolites can be microbial toxins which are converted into toxoids, subunits of pathogens, recombinant proteins resembling portions of the pathogenic microbes including virus-like particles (VLPs), peptides, carbohydrates of various kinds emanating from the pathogens as well as conjugates thereof.
Attenuated microbes are more immunogenic than the inactivated pathogens or the protein-based antigens, selected from portions of pathogenic microbial metabolites or body-parts. Antigens which are not protein-based especially certain carbohydrates, polysaccharides, oligosaccharides, small peptides, haptens and others which are not sufficiently immunogenic need to be modified by conjugation with certain proteins which are then easily recognized by the immune cells. In general all the conjugate vaccines are manufactured by linking certain proteins to the disease-specific antigens belonging to the classes of polysaccharides, oligosaccharides, peptides, haptens and others in order to enable an ennance the antigen presentation phenomenon to the immune cells to activate the immune system to produce the necessary effector B and T cells to recognize the pathogens and to act against those to resist infection.
Development of vaccines against certain infectious diseases such as those caused by Haemophilus influenzae type b, Streptococcus pneumoniae and Neisseria meningitidis requires enhancement of the polysaccharide-based antigens of these microbes to make those more immunogenic. Multiple kinds of proteins can be chosen for this purpose such as the diphtheria protein CRM, diphtheria toxoids, tetanus toxoids, Neisseria meningitidis outer membrane complex, and Haemophilus influenzae protein D. Immunogenicityof the covalently conjugated polysaccharides in the process gets substantially enhanced. The best one needs to be chosen, taking into consideration the overall property enhancement of the conjugate vaccine including ease of antigen presentation, induction of immunologic memory, reduction of nasopharyngeal colonization and herd immunity, antibody avidity and avidity maturation as also cost consideration. Conjugation technology has paved the way to develop more effective vaccines against certain infectious diseases.
The activities of several of the antigens are further enhanced by using these along with adjuvants that positively modulate their presentation to the antigen presenting cells of the immune system. The aluminium compounds such as aluminium hydroxide and aluminium phosphate are widely used as adjuvants for a number of vaccines. Presently, there are five licensed vaccine adjuvants which include besides the aluminium compounds, MF59 (oil-in-water preparation containing squalene, originally obtained from shark liver oil but presently have multiple sources), ASO3 (squalene-based adjuvant), ASO4 (a combination of TLR4 agonist 3-O-desacyl-4’-monophosphoryl lipid A and aluminium compounds) and certain types of virosomes. Use of an effective adjuvant enables the development of acquired immunity in less number of vaccine applications. The concept and the benefits of adjuvantsin vaccination process have been reviewed with special focus towards the prospects of controlled release of antigens. Presently, several vaccine-formulations are marketed to protect from a single disease (one individual disease) or vaccineformulations of multiple antigens for protection in one shot from multiple diseases, Vaccination of people with greater coverage of children and other vulnerable subsets of individuals, leads to healthier and more productive population.
RESEARCH AND DEVELOPMENT
Indian research is focused on developing the vaccines which are available in India through imports but are not manufactured yet in the country, with the objective of import substitution. In cases where the vaccine is protected under IPR, the development for a substitution can start in advance taking into consideration the expiry date of the IPR and becoming ready for market-introduction soon after the expiration of the patent. The driving force is to beat on prices and capture the market share as the imported vaccines are very expensive. India can reduce the costs substantially because when an efficient technology is developed, the costs can be cut down sizably through savings in civil construction and capital goods costs, skilled-manpower costs, certain raw and packing materials costs and costs of ancillaries. Moreover there exists a local market.The development cost is also lower since highly skilled modern biologists including microbiologists, chemists, chemical and biochemical engineers are abundantly available. Several hospital settings and patient population exist for high quality clinical data generation at much cheaper costs. However, the existing infrastructure falls short when a totally new vaccine is to be developed for the first time. For such a development neither the industry nor the institutional infrastructure has the necessary resources. The risks on investment are enormous for such kinds of research work as failure rates are very high.
There is an urgent need for the Indian companies to develop certain vaccines on a priority basis which include vaccines against pneumonia from Streptococcus pneumonia; dengue virus; human papilloma virus (HPV); chicken pox and herpes zoster virus : malaria : HlV; tuberculosis; respiratory syncytial virus (RSV); enterotoxigenic Escherichia coli (ETEC); shigella; norovirus; zika virus; chikungunya virus; and Ebola virus. India needs to intensify its R&D efforts for developing vaccines against these diseases. Many of the above mentioned diseases which are not presently a threat in India, are spreading quite fast across countries due to increase in trade and people’s movement.
Much of the research at company level is carried out at certain companies such as Serum Research Institute of India, Pune; Biological E. Ltd, Hyderabad; Shantha Biotechnics Ltd., Hyderabad; Bharat Biotech, Hyderabad; Panacea Biotec, New Delhi etc among others. The focus is on the development of single and multiple antigen vaccines at more competitive prices; development of carbohydrate-based conjugate vaccines as also certain viral disease preventive vaccines such as Hep-B vaccine, influenza virus vaccine and rotavirus vaccine are also on sharp focus. Several other research efforts through international collaborations as also through local institutional efforts are also being pursued through government efforts. The efforts of the Department of Biotechnology (DBT), Government of India and those of Indian Council of Medical Research (ICMR) through their institutionsare significant.
The profound strength of the Indian vaccine manufacturers emanates from the availability of low cost highly skilled manpower, capability to develop and produce high quality vaccine products, availability of multiple starting materials including plastics and other packing materials locally, prefilled syringes at competitive prices, availability of small animals at competitive prices (which are used in quality assurance and quality control endeavor) and efficiency in engineering capabilities. The costs of pre-clinical as well as clinical trial are also considerably low. The vaccines manufactured are primarily the conventional ones; certain modern recombinant DNA based vaccines as also conjugate vaccines have also been added and are being manufactured by multiple Indian companies.
Indian vaccines industry has a large internal market to be serviced. The market includes the sale of vaccines for utilization in the Universal Immunization Program (UIP) of the government and the trade market. On the export front, because of various other reasons including WHO certification of multiple numbers of Indian vaccines as also the manufacturing premises, which maintain WHO compliant standards and further, because the production-costs are low, the Indian manufacturers are in a position of exporting a sizable quantum of their production annually.
In India most of the diseases of the developing world are found including a host of neglected diseases. India is also the hub of emerging modern pharmaceutical companies as it has world-class scientific capabilities. India has jumped on modern biotech bandwagon and is poised to emerge as a strong player in modern biotechnology. Indian intellectuals have been supporting science as a tradition and this became more intense over time after the country’s independence in 1947. India is however in stiff competition with China, South Korea, and certain Latin American countries like Brazil, Argentina and others in its efforts towards developing cost-effective vaccines. The MNCs directly are not intense in their race for capturing the developing-country markets for vaccines as the profit-margin is low; but some major MNCs have either purchased or have acquired major share in certain companies in the strategic developing countries so as to ease the sale of their own products there on one hand and to carry out some developmental work at low costs at those countries utilizing the local talents and using the local business environment. This is also true in India. At this crucial juncture therefore, Indian research needs to be intensified to work on the development of vaccines to protect people from the attack of multiple numbers of pathogens, endemic to the developing world. While Indian efforts continue to intensify through in-country research carried out at manufacturing units, other efforts such as those made through local institutions singularly or through international collaborations are also significant but need to be intensified with allocation of more funds in order to achieve faster impact.
“Any error in this manuscript is silent testimony of the fact that it was a human effort”.
Dr. Wahied Khawar Balwan
Senior Assistant Professor
Department of Zoology
Govt. PG College Bhaderwah