Vaccines can greatly prevent infectious diseases. Between 1924 and 2010, 103 million childhood diseases were prevented in the United States through vaccination alone. In particular, smallpox was eliminated by vaccines in 1980, which was one of the greatest achievements in the history of medicine. Before that, smallpox had endangered humans for at least 3,000 years, killing 300 million people in the 20th century alone. Vaccines can prevent diseases caused by a large number of viruses and bacteria, while vaccines against parasites are being developed. Vaccines are also one of the most effective investments. $1 dollar expenditure on vaccines is estimated to generate an economic return of $44 by ensuring that a child grows up healthily and reach his/her full potential.
1. The Development of Vaccine Science
In 1798, Edward Jenner published his book entitled An Inquiry into the Causes and Effects of the Variolae Vaccinae, which was the first scientific description of vaccines, marking the birth of vaccine science. It is worth noting that smallpox vaccination had existed in China, India and Turkey for centuries before the wife of the British ambassador to the Ottoman dynasty, Ms. Mary Montague, introduced the smallpox virus to the West. The vaccine itself, including the substance that injects vaccinia vesicles into healthy individuals, was first demonstrated by a British farmer Benjamin Jesty, about 25 years before Jenner’s vaccine. Jenner’s vaccination technique was relatively widely used in the 19th century.
Modern vaccine science is developed by Louis Pasteur who first developed a chicken cholera vaccine in the laboratory. In 1879-1880, Pasteur used chicken soup to develop a chicken cholera vaccine that could be produced in the laboratory. Five years later, he went on to develop a human rabies vaccine.
The next big innovation came from American scientists Daniel Elmer Salmon and Theobald Smith, who pioneered the development of vaccines that kill pathogens. Then, at the end of the 19th century, scientists developed vaccines against typhoid, cholera, and plague. In the 20th century, more and more infectious diseases such as rotavirus can be prevented by vaccines. These vaccines are either live attenuated vaccines with completely inactivated pathogens, or subunit vaccines that contain antigens (such as proteins, polysaccharides or conjugates) but do not contain the rest of the pathogens. In 1986, the first genetically engineered vaccine made great progress—the advent of recombinant hepatitis B surface antigen vaccine. It was not until recent decades when vaccines are developed using empirical methods. With the increasing popularity of sequencing and bioinformatics tools, researchers pay more attention to reasonable methods of vaccine design.
2. History and Science of Adjuvants
Vaccines were used successfully before people understand how vaccines work. Live attenuated vaccines alone are sufficient to produce strong and lasting immune response. In the development of diphtheria and tetanus recombinant protein vaccine, the antibody response induced by isolated injection of these proteins is very weak and short-lasting. French veterinarian Gaston Ramon, a former director of the Pasteur Institute, has repeatedly noted that vaccinated horses produce a better immune response if there is inflammation at the injection site. Later, Ramon found that certain substances, such as cassava powder, lecithin, agar, starch oil, diosgenin or bread crumbs could be added to the vaccine to improve the immune response. Then scientists found that diphtheria toxoid precipitated with aluminum salts could lead to a significant increase in immune response. Since then, aluminum salts became the main component of adjuvants, and until 20 years ago, the clarity of the molecular mechanism of adjuvants further promoted the development of new adjuvants.
We know that live attenuated vaccines and inactivated vaccines to some extent work well because they provide two necessary signals to induce immunity, which are antigens and natural adjuvants. Antigens indicate the specificity of adaptive immune responses to specific pathogens, while adjuvants stimulate the innate immune system through the pattern recognition receptors (PRRs), and PRRs recognize pathogen-related molecular patterns (PAMPs). In order for the antigen to have immunogenicity, the antigen must be accompanied by PAMPs that can trigger PRRs in the antigen presenting cells. The innate immune recognition of PRRs can produce the signals needed to activate adaptive immunity, which explains why adjuvants are needed in vaccines. PRRs include Toll-like receptors (TLRs), cytoplasmic virus nucleic acid sensors (such as RIG-I and cGAS), and other receptors that detect the activity of pathogens. Based on the pioneering work of Ralph Steinman, we now know that dendritic cells are the key cells that trigger the adaptive immune response.
By understanding the mechanism by which adjuvants enhance the immune response, it is possible to design adjuvants to achieve the desired results. At present, several adjuvants are licensed for human vaccines. In addition to alum, TLR agonists, monophosphoryl lipid A (MPL, a TLR4 agonist), and CpG 1018 (TLR9 agonists) have been approved for use as vaccine adjuvants. In addition, adjuvants currently in use include viral bodies, MF59, ISA51, and a range of AS adjuvants developed by GlaxoSmithKline, including AS01 (liposomes of MPL + QS- 21), AS04 (3-deacyl-MPL), and AS03 (vitamin E/surfactant polysarboxylic acid 80/squalene). For SARS-CoV-2 vaccines, there are other adjuvants at all stages of clinical trials, including Matrix M and Advax. At present, the large number of clinical trials of COVID-19 vaccines provide an excellent opportunity to evaluate the safety and efficacy of these new adjuvants.