Emerging Trends and Challenges in Vaccine Development and Manufacturing
Prof. Shailendra K Saxena
Centre for Advanced Research (CFAR)-Stem Cell/Cell Culture Unit
King George's Medical University (KGMU)
Amrita Haikerwal
Centre for Advanced Research (CFAR)-Stem Cell/Cell Culture Unit
King George's Medical University (KGMU)
Swatantra Kumar
Centre for Advanced Research (CFAR)-Stem Cell/Cell Culture Unit
King George's Medical University (KGMU)
Madan LB Bhatt
Centre for Advanced Research (CFAR)-Stem Cell/Cell Culture Unit
King George's Medical University (KGMU)

Vaccines are the most robust and economical means of reducing the cases of emerging infectious diseases. However, major challenges during vaccine development include insufficient preclinical data, constant updating (antigenic variation) of vaccine formulations, adverse effects/hypersensitivity, storage and preservation especially cold chain maintenance. Similarly, lacks of meaningful market motivation, reduced investments in vaccine R&D are the cost-benefit obstacles for the vaccine manufacturers. The global health organizations should provide the necessary support to the industries for the advancement and rational development of vaccines for eradication of the emerging infectious diseases.

Vaccines are the most promising approach of developing preventive therapeutics strategies in order to alleviate the worldwide load of communicable diseases[1]. The preventive mechanism of current available vaccines can be explained by the ability to stimulate the antibodies which can neutralize the infectious etiological agents upon natural infection. In 1983, 99 per cent reduction in measles cases has been achieved in United States using Measles vaccine[2]. Similarly, a great achievement has been attained in case of Polio, Tetanus and smallpox through effective vaccination strategy[3].

Vaccine can be broadly classified into various categories such as Live attenuated; Inactivated; Subunit; Toxoid; Conjugated; DNA and Recombinant vector vaccine[4]. Antigenicity of a vaccine can be enhanced by using an adjuvant which can be described as substances used in combination with specific antigens eventually results in robust immune response. On the basis of its mechanism adjuvant can be broadly divided into delivery systems and immunestimulatory adjuvant. Various substances have been utilize as an adjuvant such as microbial products, mineral salts, saponins, polymers, emulsions, microparticles and liposome[5]. Generation of a live attenuated vaccine (LAV) can be achieved by attenuating the naturally existing viruses[6]. Unlike LAV, less immunogenic inactivated vaccines are generated by killing the etiological microbial agents with radiations, chemicals and heat[7]. Subunit vaccine can be developed by including only the immunogenic antigens with the advantage of lower adverse effects[8]. Toxoid vaccine is successful vaccination strategy exploited in case of bacterial infections secreting toxins[9]. Furthermore, conjugate vaccines are the special type of toxoid vaccine targeting bacterial infections where a polysaccharide coating is used to disguise the bacterial antigens[10]. The relatively easy and inexpensive to design DNA vaccine are the most effective strategy used to stimulate strong immune response[11]. Recombinants vaccines are the DNA vaccines along with vectors such as virus or bacterium[12].

The developmental process of a vaccine can be broadly categorized into 2 stages; Preclinical and Clinical development. Preclinical development process includes Reverse vaccinology (identification of relevant antigens), creation of a vaccine concept, determination of effectiveness in animal models, and manufacturing of the vaccine under GLP facility. Whereas clinical development process include clinical trials in human subjects (Phase I-IV)[13]. Approximately, 50 licensed vaccines are available for human use and 50 per cent of them are prescribed widely. The arena of vaccines has long been neglected from a commercial perspective because of several factors including insufficient preclinical data, constant updating (antigenic variation) of vaccine formulations, adverse effects/ hypersensitivity, storage and preservation especially cold chain maintenance. Similarly, lacks of meaningful market motivation, reduced investments in vaccine R&D are the cost-benefit obstacles for the vaccine manufacturers.

Challenges in Vaccine Development and Manufacturing

The production of a successful vaccine for an infectious disease is the tip of an iceberg that comes after facing numerous challenges at different levels of vaccine development and manufacturing. The determination of potential target antigen, antigenicity, competent immune response,

generation of antibodies, insufficient data from the pre-clinical trials, genetic variation of antigens[14], and in some special cases vaccines can cause antibody-dependent enhancement of infection[15] [16], are the challenges experienced during the generation of vaccines from the research perspective. Likewise, the industries involved in development and manufacturing of vaccines have to deal with the cost-benefit obstacles such as the long-term source of investment for vaccine production, urgent bulk productions in case of outbreaks and pandemics, storage and safety facilities. Some of these challenges are:

1. Lack of Motivated Market

The requirement of vaccines has increased on a global scale due to rising number of cases of infectious diseases along with the genetic variation, assortment and evolution of infectious agents, despite the fact, only few leading pharmaceutical industries (such as Merck & Co. Inc., GlaxoSmithKline, Sanofi Pasteur, and Wyeth) have the facilities and strength to develop and manufacture new vaccines. To accommodate the rising demand, small industries such as Berna Biotech, Baxter, Chiron and Acambis have emerged for the development of new vaccines. The major challenges faced by the small industries is to develop a vaccine product in accordance with the stringent regulatory norms, as the safety and effectiveness of the vaccine are imperative, considering the fact that it has to be administered in healthy new-born babies, children, and adults unlike the drugs are given to individuals with disease. Moreover, the establishment of the complex state of the art technologies, expensive hightech facilities and apex level laboratories are required for taking the pilot-scale of vaccine generation to bulk preparation. The regulatory body assures that the quality of every dose of vaccine-generated is with uniform efficacy and safety. Thus, with the support of leading health organizations and funding agencies, availability of vaccines could be rapid as several small industries will be willing to participate[17].

2.Preparedness for Outbreaks and Pandemics

The global alertness during outbreaks and pandemics has been improvised due to continuous monitoring of number of incidences of infectious diseases reported in the surveillance systems that provide authenticate data for estimating the severity of disease. Vaccines are the ultimate weapon to combat the outbreaks from turning to pandemics, however, the immediate requirement of new vaccine candidate for the emerging infectious agent becomes a cumbersome task for the pharmaceutical industries[18].
Collaboration between a research team comprising of scientists, bioprocess engineers, academicians and industries in short period of time is itself a difficult task for the preparation of safe and effective final vaccine product[19]. The development of a robust and practical vaccine requires a thorough research at both in vitro and in vivo levels, genome sequencing of the infectious agent, identification of the correct antigen for vaccine preparation in a limited period of time, and furthermore maintaining the consistency of vaccine obtained at in vivo stage to the final product. The pharmaceutical industries require a lucrative source of funding to facilitate themselves with advanced technologies for providing immediate and effective vaccine candidates which is another very crucial factor.

3. Cost-benefit vs. Risk-benefit

development require a huge investment, resulting abandonment of small scale industries in mid-way of discovering a potential vaccine candidate. Despite the fact of high cost of vaccine development, the benefit of patent protection on the new vaccine is for a limited period of time which leaves the pharmaceutical industries in dilemma of analyzing the cost-benefit ratio[20]. With the very low cost of vaccines in developing or low-income countries, the pharmaceutical companies are worried regarding their trafficking to the developed countries which will be a setback for their business. The risk associated with manufacturing of vaccine is at every step from characterization of the correct potential antigen candidate to the maintenance and precise performance of the concerned equipments. A wrong judgment or a misstep prone to error at any stage could ruin this time consuming and expensive process of vaccine development. Preparation of vaccine involves consideration of factors such as the molecular weight of the potent antigen which is 10,000 times greater than the size of the pharmaceutical drugs as well as the its biological activity to generate the immune response. Manufacturing of such large molecules require extensive analytical analysis and clinical testing by the regulatory bodies to reassure the equivalence of every batch of vaccine in terms of potency and safety.

Bridging the Gap Between Vaccine Development and Challenges Associated with them

In current scenario, vaccines are not only targeting the emerging infectious diseases but also other spectrum of chronic infections, cancer, neurodegenerative diseases, and tumors. Besides, vaccine could be given at all ages and also to the impoverished populations living in developing countries to enhance their quality of life. The economic crisis has cut down the healthcare budget and left the policy makers and decision-making bodies in dilemma in order to understand/calculate the value of vaccines. One of the platforms for calculating the value of vaccination is Strategic Multi-Attribute Ranking Tool for Vaccines (SMART) developed by Institute of Medicine, for improvising the decision making for resolving various difficult attributes of vaccination[21]. With the advanced scientific approaches such as bioinformatics, genomic and proteomic studies, better understanding of the concerned disease could be conducted for rational designing of the vaccine.

The discovery of vaccine from an early stage involves lucrative financial support from funding agencies to the pharmaceutical industries. The corporate social responsibility of eminent companies could be utilized by the healthcare officials for vaccine development during outbreaks of infectious diseases. All the essential components for the vaccine development such as antigens (active component), adjuvants, diluents, stabilizers, preservatives, trace components (egg proteins, yeast, antibiotics, research team, advanced instruments/technologies, regulatory body, bulk production facility should be enabled in an industry for rapid manufacture of new vaccines.

Conclusions and Future Perspectives

Emerging new infectious diseases and antigenic variation among the circulating infectious agents have limited the prosperity of Antibody mediated protection, suggesting that we need to focus on various ways to develop advanced vaccines with robust efficacy and safety. In order to achieve, several approaches such as reverse vaccinology, adjuvant development, and vector design have provided an opportunity to the preclinical developmental process for a successful vaccine candidate formation. Lack of resources at the critical stages of the preclinical developmental process is indicating the urgency for the new funding, the most imperative factor in vaccine industry. Establishment of a Global vaccine development fund may accelerate the development of new and improved vaccines. Investment of USD 2 billion a year may cut down the global health risk and reduces the disease burden worldwide.

Acknowledgments

The authors are grateful to the Vice Chancellor, King George's Medical University (KGMU), Lucknow and Director, Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research (CSIR-CCMB), India for the encouragement and support for this work. S K Saxena is also supported by CCRH, Government of India, and US NIH grants: R37DA025576 and R01MH085259. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Conflict of Interest: None

Abbreviations:Live attenuated vaccine (LAV), Strategic Multi-Attribute Ranking Tool for Vaccines (SMART).

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