Early vaccine studies
Initial vaccine attempts to prevent infectious diseases were in 1000 AD in China, whereby the contents of smallpox vesicles were used to inject healthy individuals who were subsequently protected against smallpox. In the late 1790s, Edward Jenner immunized an 8-year-old boy with cowpox and then challenged him with smallpox; the boy was found to be immunized against smallpox. Thus, cross-reactivity from one species of smallpox to another species of smallpox resulted in protective immunity. During the 19th Century, smallpox vaccination became increasingly popular and eradication was accomplished in the decade of 1967–1977. In the last quarter of the 19th Century, Louis Pasteur noted that by attenuating a pathogen from cholera, it was possible to administer the attenuated strain as a vaccine. The first attenuated bacterial vaccine used in humans in 1884 was against cholera. Although the vaccine was given to approximately 30,000 individuals, most of whom were protected, severe side effects occurred and its use was halted. Pasteur and colleagues also worked with viruses, especially rabies. They noted that if the spinal cords were dried for 2 weeks, they lost their ability to induce rabies. An immunization schedule was set up with 42 dogs and, although the results were extraordinary, the vaccination procedure was quite controversial in that deaths occurred in some animals. Another approach was to use killed viruses as a vaccine, such as the poliomyelitis vaccine (Salk), which involved treating the virus with formalin. This vaccine had a big impact on the incidence of the disease prior to it being replaced by the live-attenuated version developed by Sabin. The Sabin vaccine was inexpensive and reliable whereas the Salk (dead) vaccine was difficult to produce with inadequate quality. Inactivated (dead) vaccines, which are easy to produce at higher potency, are now available but are impractical at a global scale, even though they may be more effective than live-attenuated vaccines. Measles and poliomyelitis vaccines have now been administered to infants and children as live-attenuated vaccines.
Disasters
Despite the progress in developing vaccines to a majority of diseases with protection being noted, there were a number of disasters in humans; in 1932, the Lubeck disaster for the bacillus Calmette–Guérin vaccine, the Bundaberg tragedy in 1928 for the diphtheria vaccine, and the Cutter disaster in 1955 for the Salk-type vaccine. All these disasters were due to improper laboratory manufacturing and handling and, consequently, these cases led to improved procedures for the safety of vaccines, and led to regulatory measures to assure proper laboratory conditions, training of personnel and improved procedures in laboratories where vaccines were manufactured. With attempts to control more complex diseases, and the need to improve vaccine safety, stability, efficacy and cost, there is pressure for more and more precisely defined vaccines.
Development of safer & more effective vaccines
Public awareness of occupational health and safety issues is now much higher than it was 50 or more years ago. Vaccines must now meet higher standards of safety and biochemical characterization than they did in the past. Some of the vaccines developed in the past would not even meet the minimum standards required today. Thus, for a vaccine regime to be successful today, one needs to use new molecular and biological techniques that have been developed in the last 10 years – these techniques are useful in the generation of new and improved vaccines. Advances in the fields of molecular biology, chemistry and immunology are now used in the development of new and improved vaccines, in an attempt to move from traditional live viral and bacterial vaccines to the theoretically ‘safer’ but ‘less immunogenic’ vaccines. The application of genetic and recombinant DNA approaches, protein production techniques and synthetic peptide chemistry has led to new and safer vaccines; however, there are still many obstacles for their clinical use. The limited immunogenicity of many of these candidates has hindered their development as potential vaccines for humans. Strategies to enhance the immunogenicity of candidate vaccines have had to be developed.
Approaches to enhancing immunogenicity
Adjuvants have been developed that, when mixed with proteins, peptides or DNA, could amplify either or both the humoral and cell-mediated immune responses to that antigen. The most frequently used adjuvant in experimental animals is complete Freund’s adjuvant. Although very effective in evoking an effective and long-lasting immune response, complete Freund’s adjuvant is not suitable for human use because it induces granulomas, fever and inflammation due to the oil and mycobacteria. There is only one registered human adjuvant (aluminium hydroxide or aluminium phosphate) which is used in the diphtheria, tetanus and hepatitis B vaccines. Aluminium salt adjuvants are limited in their use in that they preclude lyophilization or freezing, they are not effective with all antigens and they do not stimulate cell-mediated immunity. Candidates for alternative adjuvants for vaccine development include: the Syntex formulation, SAF-1 (containing squalene oil, an amino acid derivative of muramyl dipeptide [threonyl-MDP] and nonionic block polymers); the Ribi formulation (containing mycobacterial cell walls and monophosphoryl lipid A); and the saponin derivative, QS21 (also called Quil A). The development of new adjuvants, however, has been dominated by concerns about safety, since most of the adjuvants that have been developed to date are too toxic for use in humans. More recently, liposomes (phospholipid-based vesicles) have been used to deliver antigens, in addition to the incorporation of antigens into solid particles such as immunostimulatory complexes. Other approaches for vaccine development include viral vectors, use of nanoparticles, targeting antigens to receptors on dendritic cells and the use of Toll-like receptor ligands to enhance immunity to the antigen. The future holds promise for new vaccines to prevent, control and possibly eradicate diseases, including cancer. All the techniques described should lead to the production of new and effective vaccines.
New-generation vaccines
The book ‘New Generation Vaccines’, by a distinguished editor and associate editors, is a timely book in this important era in the development of new-generation vaccines. The book includes 89 up-to-date chapters in the development of vaccines. The chapters are clear and informative, with key tables and figures.
The book begins with a chapter on historical perspectives and immediately enters into modern methods of defining vaccine antigens by reverse vaccinology. Initial clinical trials are evaluated, issues required for vaccine trials in developing countries are addressed, clinical trials into Phase III and IV are evaluated, ethical considerations are discussed, the economics of clinical trials are mentioned, an industry perspective is given on the development of vaccines, and achieving global immunization is discussed. The paradigm of global alliance for vaccines and immunization is nicely presented, followed by an economic analysis of vaccine programs, US FDA licensing of vaccines, vaccine safety and manufacturing, and the work of the WHO is analyzed. Efforts into the eradication of polio are discussed and recent immunological advances that impact vaccine development are assessed.
This is followed by 23 chapters discussing the modulation of innate immunity, immunodominance of antigens, measurement of T-cell responses, assessment of multivalent vaccines, vaccination and developing autoimmunity, adjuvants, Toll-like receptor agonists for enhanced immune responses, mucosal vaccines, nanoparticles, lipopeptide vaccines, use of dendritic cells to deliver vaccines, viral vectors, DNA vaccines, prime–boost approaches and transcutaneous vaccine delivery systems.
The next 44 chapters discuss specific vaccines developed for numerous diseases of bacterial and viral origin. These include vaccines against meningococcus, influenza, Salmonella, cholera, TB, dengue, rotavirus, measles, HIV, hepatitis C, respiratory syncitial virus, cytomegalovirus, Epstein–Barr virus, herpes simplex, rheumatic fever, Streptococcus, Shigella, Escherichia coli, Staphylococcus aureus, Chlamydia trachomatis, malaria, Leishmania, schistosomiasis, Entamoeb histolytica, hookwom, smallpox, anthrax, tularemia, plague, Ebola and Marburg viruses, lassa fever, hantavirus and SARS.
The final five chapters touch on the development of cancer vaccines, including the approved vaccine against cervical cancer, vaccine development against Alzheimer’s and other neurodegenerative diseases, and against autoimmune and chronic inflammatory disorders. The final chapter discusses an interesting topic in the use of vaccines to treat drug addiction.
Overall, the book addresses a range of important issues in the development of new-generation vaccines. It provides a solid overview of vaccine development and is greatly useful to a range of target audiences, such as immunologists, molecular biologists, chemists and investors in pharmaceutical companies who are interested in the development of new-generation vaccines.
Financial & competing interests disclosure
Vasso Apostolopoulos would like to thank the Susan G Komen for Cure Breast Cancer Foundation (USA), Bosom Buddies Breast Cancer Foundation (Australia), and the Beauties and the Beast (Australia) for providing funding directly to her laboratory for the development of breast cancer vaccines. The author has 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.
No writing assistance was utilized in the production of this manuscript.