From empiricism to rational design: a personal perspective of the evolution of vaccine development

Abstract

Vaccination, which is the most effective medical intervention that has ever been introduced, originated from the observation that individuals who survived a plague or smallpox would not get the disease twice. To mimic the protective effects of natural infection, Jenner - and later Pasteur - inoculated individuals with attenuated or killed disease-causing agents. This empirical approach inspired a century of vaccine development and the effective prophylaxis of many infectious diseases. From the 1980s, several waves of new technologies have enabled the development of novel vaccines that would not have been possible using the empirical approach. The technological revolution in the field of vaccination is now continuing, and it is delivering novel and safer vaccines. In this Timeline article, we provide our views on the transition from empiricism to rational vaccine design.

Figure 1. A timeline of the history of vaccines showing the technologies that have enabled their development.

Vaccine research can be divided into two main periods, with the first being the empirical approach, which was based on isolating, inactivating and injecting the microorganisms that cause disease. The second, modern approach began in the 1980s, when new technologies enabled advances in vaccine development that would not have been possible using the empirical approach. Closed boxes indicate licensed vaccines or vaccination practices that are already used. Boxes with a dashed border indicate vaccines that are still in development. BCG, Bacille Calmette–Guérin; C. difficile, Clostridium difficile; CMV, cytomegalovirus; E. coli, Escherichia coli; H. influenzae, Haemophilus influenzae; HBV, hepatitis B virus; HPV, human papilloma virus; MenACYW, meningococcus serogroups A, C, Y and W; Pneumo7, 7-valent pneumococcus vaccine; Pneumo13, 13-valent pneumococcus vaccine; RSV, respiratory syncytial virus; S. aureus, Staphylococcus aureus; TB, tuberculosis; TLR, Toll-like receptor. PowerPoint slide

Figure 2. Glycoconjugate vaccines.

a | Polysaccharides that are present on the surface of capsulated bacteria are composed of many identical repeating units of simple sugars (represented by red circles). b | When purified, the polysaccharides are poorly immunogenic, as they are unable to enter the cavity of MHC molecules and therefore they fail to be presented to T cells. In conjugate vaccines, such as those against Haemophilus influenzae type b, pneumococcus, meningococcus and group B streptococcus, polysaccharides are covalently linked to proteins. The peptides that are derived from the proteins (represented by blue triangles) enter the cavity of the MHC molecule and engage the T cell receptor directly (bottom right) or function as an anchor for a sugar epitope (top right). Figure from Ref. , Nature Publishing Group. PowerPoint slide

Figure 3. Reverse vaccinology applied to meningococcus serogroup B.

The genome sequence of meningococcus serogroup B is mined to predict genes encoding vaccine candidate antigens that are exposed on the surface of bacteria, that are antigenically conserved and that do not contain sequences that are similar to human proteins. The selected genes are expressed in Escherichia coli and then the proteins are purified and used to immunize mice. The sera of the mice are tested for their ability to kill bacteria in the presence of complement. The 'best' antigens are then selected for vaccine development. PowerPoint slide

Figure 4. Structural vaccinology for respiratory syncitial virus.

The respiratory syncitial virus fusion (F) protein is unstable and flips easily from the pre-fusion conformation that is present on the surface of the virus (left) to the post-fusion conformation (right). The pre-fusion conformation contains more neutralizing epitopes and is preferred for vaccine development. Once the crystal structure of the pre-fusion and post-fusion conformations had been determined, it was possible to stabilize the pre-fusion conformation by introducing a cysteine at two amino acid residues (Cys155 and Cys290) that are closely spaced in the pre-fusion conformation but very distant in the post-fusion conformation (shown by red dots). The two cysteines in the pre-fusion conformation form a disulphide bridge and lock the protein in the pre-fusion state. From McLellan, J. S. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 342, 592–598 (2013). Reprinted with permission from AAAS. PowerPoint slide

Figure 5. Synthetic biology for influenza vaccines.

Timeline of the 2009 influenza virus pandemic showing that by using the conventional technologies at that time, large quantities of vaccine became available only after the peak of the viral infection. The dashed lines indicate the hypothetical time course for vaccine production from synthetic seeds and the synthetic self-amplifying mRNA (SAM) system, which might help to produce large quantities of vaccine in the future before the peak of influenza infection. Figure adapted from Ref. , with permission from AAAS. Data from Refs , ; Douglas Jordan/Centers for Disease Prevention and Control. PowerPoint slide