The ideal vaccine would induce a robust immune reaction against a pathogen without serious adverse effects. Personalized vaccines are becoming a focus of study as they promise to fulfill these criteria, aided by in-depth genetic studies of variation in immune responses – vaccinomics.
“The next ‘golden age’ in vaccinology will be ushered in by the new science of vaccinomics. In turn, this will inform and allow the development of personalized vaccines, based on our increasing understanding of immune response phenotype: genotype information."
Poland et al., 2008
Background
At present, universal immunization is practiced, using the same vaccine formulations, the same doses, and the same number of doses, for an entire population, provided there are no contraindications. This assumes that everyone will have the same kind of immune response, achieve comparable levels of immunity, whether antibody or cell-mediated and that all will require the same level of antigen to develop immunity. It also assumes the same level of risk for everyone.
The outcome of this approach is the extremely high vaccine uptake due to the automatic administration of vaccines to almost everybody, leading to the control of many communicable diseases. Conversely, it does not take into account individual variability in the risk of disease, immunologic response, adverse reactions, and dosage or interval between doses.
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Characteristics of Personalized Vaccines
What is a personalized vaccine? This term refers to the adaptation of vaccine antigens to optimize the outcome, that is, maximal immunogenicity with minimal vaccine failure or adverse reactions, in a host who is at risk of severe disease or complications.
There are many barriers to personalized vaccine development, including a lack of data on the development of the immune response; genetic variability among both pathogens and hosts, affecting the immune response; environmental factors such as obesity; geographic factors such as the difficulty of maintaining a cold chain in tropical climates, which could reduce vaccine usage or efficacy; and licensing or regulatory issues.
This has hampered the development of vaccines against pathogens that show high variabilities, such as Mycobacterium tuberculosis, Plasmodium, hookworm, human immunodeficiency virus (HIV), hepatitis C virus (HCV), and the coronaviruses.
Personalization of a vaccine could mean that the immune response may not be robust, or that serious adverse reactions could occur, in the presence of a certain polymorphism, such as a single nucleotide polymorphism (SNP) that affects the amino acid sequence at functional sites of a protein involved in the immune cascade; or a certain haplotype.
It is universally noted that females respond with higher antibody levels than males, following vaccination. Race/ethnicity also plays a role, with Native Alaskans and Native Americans responding poorly to polysaccharide vaccine antigens because of a genetic polymorphism. Again, genetic factors could block the immune response to a vaccine antigen because of a drug being taken concurrently, which prevents the transcription of an immune response gene.
To look ahead, some researchers expect the advent of a vaccine era, with the ability to quantify and predict immune responses, that can shape clinical practice. This will depend on the availability of inexpensive, accurate, and reproducible tools that can sequence the genomes rapidly, building a database of linked genotypes and phenotypes, along with the right programs to carry out bioinformatics and statistical analyses.
Personalized vaccines are likely to improve clinical outcomes by enhancing the immunogenicity, reducing side effects, and saving on healthcare expenses. In the pursuit of such vaccines, vaccinomics plays a large role.
It shows how many key immune genes show polymorphisms that affect the immune response via multiple mechanisms. It also demonstrates the effect of selection pressures on enhancing the type and number of such polymorphisms, to broaden the range of immune responses to infectious pathogens.
Scientists are continuing to use vaccinomics to uncover how these genes will affect the genome-wide activation or modification of the immune response while recognizing that few such polymorphisms are dominant in their on-off effects on this pathway. Rather, they explain how individuals show differences in their immune response to the same antigen.
Personalized vaccines are not aimed at single individuals but groups based on the same gender, genotype, and other factors. This entails a realization of vaccine safety, prediction of adverse events, host-pathogen interactions, and the recognition of the diversity of the individual’s immune response.
HLA Polymorphisms
The human leukocyte antigen (HLA) complex determines whether the immune system recognizes antigens as “self” or “non-self”. This complex of genes on chromosome 6 encodes the genes with the highest level of polymorphism. In the HLA-A, -B, and -C loci, over a thousand alleles have been described. The HLA system is considered key to the different immune responses to the same vaccine seen in different individuals and groups.
Following vaccination, HLA class II alleles regulate the antibody response, since they present the antigens that are recognized by and activate CD4+ T cells, which in turn promote antibody production by cognate B cells.
Single nucleotide polymorphisms (SNPs) are the most frequent type of gene variation, making up 90% of the variation in the genetic makeup between individuals. When non-synonymous SNPs occur in coding regions, or regulatory regions, they may directly affect the protein structure and function that determine the type and presentation of the antigenic epitopes.
Some examples offered by the history of vaccination include the use of adjuvants that activate some Toll-like receptors (TLRs) such as TLR9 or TLR4, thus bypassing other receptor-mediated restrictions on cell activation. Different alleles of these genes could thus alter the immune response to measles vaccine antigens, for instance.
Cytokines, or inflammatory mediators, are also regulated by the rate of transcription of their genes, and SNPs here can disrupt transcription factor binding, modulate gene expression or alter gene function by destabilizing ribonucleic acid (RNA) molecules. This type of polymorphism could be bypassed by developing new vaccine candidates incorporating cytokine plasmids or adjuvants, such that the Th1/Th2 balance is achieved.
Identifying genetic markers for higher risk of adverse reactions could be useful in screening individuals pre-vaccination, to help determine the risk-benefit ratio in each case. However, developing and using different vaccines for different groups of people in this manner could be both more cumbersome and more expensive, though it would save later costs due to breakthrough infections and the treatment of serious adverse effects, for example.
A more serious objection is the need for each of these vaccines to be licensed separately, per vaccine type, dose and schedule. One workaround could be to develop cocktails of vaccine peptides with suitable adjuvants, such that different individuals will respond to different vaccine agents. The agents themselves could be included based on the population-level HLA type.
As next-generation sequencing platforms become less expensive, it may become possible to determine the individual’s microbiome profile within a clinical setting that will shape the composition of the personalized vaccine. The development of such a vaccine would require a shift from empirical methods to a perspective based on a deeper understanding of innate and adaptive immunity, and of the host risk of infection mediated by the genetic and environmental profile.
The new science of personalized vaccines | Ofer Levy
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Further Reading
The path to a better tuberculosis vaccine runs through Montana