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Chapter 18
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Use of Nanotechnology in the Formulation
of Vaccines
Yvonne Perrie and Cameron Webb
18.1 Immunity and Vaccination
Infectious diseases remain among the leading causes of death worldwide and
vaccination offers one of the most effective strategies in global healthcare to address
this. Vaccines harness the capacity of the human immune system to recognise and
remember encounters with pathogen antigens. Despite rapid developments in vaccine technology, there is an urgent need for more vaccines targeting challenging
pathogens like Mycobacterium tuberculosis (the causative agent of tuberculosis).
Moreover, it is essential to address antigenically diverse pathogens such as HIV,
control outbreaks that pose a global health security threat (such as Ebola), and
explore strategies to reinvigorate immune responses within the ageing immune
system.
Nanoparticles have emerged as pivotal components in vaccine development,
offering significant contributions to various vaccine platforms, including mRNA
vaccines. Nanoparticles offer unique properties that enable them to play a crucial
role in enhancing the effectiveness and efficacy of various vaccine formulations.
Given their versatility, nanoparticles can encapsulate and protect vaccine components, whether they are viral proteins, bacterial fragments, nucleic acids, or other
immunogenic components. This protection shields antigens from degradation and
facilitates appropriate cell delivery, thereby driving potency. Additionally,
nanoparticles can be engineered to mimic the size, shape, and surface features of
pathogens, thereby activating specific immune pathways and promoting potent
immune responses. Surface modification of nanoparticles can also promote the
Y. Perrie (✉) · C. Webb
Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde Institute of Pharmacy
and Biomedical Sciences, University of Strathclyde, Glasgow, UK
e-mail: yvonne.perrie@strath.ac.uk
© The Editor(s) (if applicable) and The Author(s), under exclusive license to
Springer Nature Switzerland AG 2024
I. F. Uchegbu et al. (eds.), Fundamentals of Pharmaceutical Nanoscience,
https://doi.org/10.1007/978-3-031-59478-6_18
485
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targeting of specific cells or tissues within the immune system, enhancing antigen
uptake and presentation to immune cells, such as dendritic cells. Finally,
nanoparticles can act as adjuvants in their own right, boosting the immune response
and promoting long-lasting immunity. This combination of characteristics makes
nanoparticles invaluable tools in the development of vaccines.
18.1.1 Developing Immune Responses
Regardless of vaccine innovation and development, the key and fundamental attribute that all vaccines commonly share is immunity against a pathogen without prior
exposure to the specific disease in question. To achieve this, the vaccine aims to
closely copy foreign pathogens’ mechanisms of action that induce the immune
response without the pathogenicity and strong immune responses associated with
the pathogen’s exposure. To achieve this, both innate and acquired immune
responses must be activated (Fig. 18.1).
Innate immunity is immunity that an organism is born with. This type of
immunity is part of our genetic profile and offers lifelong protection. The innate
immune response is fast-acting and non-specific, so it responds the same irrespective
of the pathogen it detects. In humans, the innate immune system encompasses
physical and chemical barriers, that provide a first line of defence with chemical
Fig. 18.1 Schematic of the three layers of immune defence. The first layer consists of physical and
physiological barriers, including the skin and mucous membranes (e.g. mouth, lung), body temperature, and differences in pH (e.g. in the stomach). If the pathogen crosses these barriers, it then
faces innate (non-specific) and adaptive immune responses. (Created with
BioRender.com)
18 Use of Nanotechnology in the Formulation of Vaccines 487
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(humoral) and cellular aspects as the second line of defence. Physical barriers that
protect us from infection include our skin, eyelashes, tears mucous, and stomach
acid. Chemical defences include complement activation and inflammatory
responses. Cellular defences within the innate immune response include phagocytes,
natural killer cells, and mast cells. Their role is to identify non-self-pathogens,
neutralise or destroy them, and activate the adaptive immune
The activation of the innate immune response characterises the initial stages of
infection. The nature of the immune response is dependent on whether the threat is
intracellular, such as a virus, or extracellular, like a bacterium. During this phase, the
innate immune response identifies potential invaders by detecting the absence of host
MHC-class I molecules that signify “self” or by recognising molecules commonly
found in pathogens but not in the host. These recognised molecules are known as
pathogen-associated molecular patterns (PAMPs) and their identification triggers
processes such as phagocytosis or cytotoxic killing to eliminate the invaders. In the
case of intracellular threats, specific receptors called pattern recognition receptors
(PRRs) detect foreign components such as viral RNA, DNA, or intermediate
products.
Consequently, the activation of PRRs leads to the production of pro-inflammatory
cytokines, the apoptosis of infected cells, or the labelling of infected cells for
targeted destruction by other innate immune cells. Phagocytic cells, including
dendritic cells, can internalise foreign substances and process them. Through this
process, these cells break down the engulfed material and display fragments of it on
their cell surfaces, which plays a crucial role in initiating the adaptive immune
response. Due to this characteristic, they are classified as antigen-presenting cells
(APCs).
When the innate immune system alone proves insufficient for controlling a
foreign threat, the adaptive immune system is triggered. In contrast, acquired
immunity is not inherent in organisms and is not genetically predet ermined, like
innate immunity. Adaptive (or acquired) immunity is acquired throughout our
lifetime due to exposure to specific antigens, either through natural means such as
infection or via vaccination. It is characterised by its specificity, memory, and ability
to mount a faster and stronger response upon re-exposure to the same antigen. Unlike
the rapid and generalised response of innate immuni ty, the adaptive immune
response is slower, taking days or even weeks to develop after initial encounter
(known as the primary immune response). However, it exhibits specificity towards
the particular antigen(s) present and can retain long-term immunological memory.
This memory allows for a quicker and more efficient response if the same antigen is
re-encountered in the future. However, adaptive immunity can wane, particularly if
there is no regular re-exposure to the antigen.
The adaptive immune system is triggered through the action of signalling molecules and/or the presentation of antigens by antigen-presenting cells. Among these
antigen-presenting cells, dendritic cells play a crucial role by displaying major
histocompatibility complex class II (MHC class II) molecules on their surface,
facilitating the presentation of foreign peptides and ensuring appropriate immune
activation. The adaptive immune response encompasses two main components: the
response.
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cell-mediated immune response and the humoral immune response. The cellmediated response is driven by T cells, which can directly eliminate infected cells
or help stimulate B cells towards antibody production. Upon activation, naïve B cells
differentiate into memory cells and plasma cells. Memory cells and plasma cells are
integral to long-term immunity. Plasma cells secrete large quantities of antigenspecific antibodies, effectively neutralising and elimina
throughout their lifespan. Memory cells, on the other hand, can persist for extended
periods, reactivating upon re-exposure to their specific targe t antigen. This
reactivation prompts the production of antibodies, resulting in a swifter and more
robust response to repeated exposures.
ting the target pathogen
18.1.2 How Do Vaccines Promote Immune Responses?
As outlined, our immune system is developed to offer a wide range of protection;
however, one issue is that during an infection the body must be able to respond
quickly and vigorously enough to provide the appropriate protection without the
individual suffering the potentially lethal consequences of the infection. To address
this, vaccines have been developed. A vaccine can be defined as a biological product
that can safely induce an immune response that promotes protection against infection
and/or disease on subsequent exposure to a pathogen (Pollard and Bijker 2021). The
goal of a vaccine is to develop long-lived immunological protection, whereby the
first encounter with a pathogen is remembered and recognised by the immune
system. Therefore, the immune system can generate a rapid, protective response
against the infection. To do this, the vaccine should contain antigens that represent
components of the pathogen. These antigens are normally protein-based and can be
derived directly from the pathogen or produced synthetically. However, polysaccharide antigens can also be used to induce immune responses. Nanoparticles can
support vaccine efficacy by protecting and delivering such antigens to immune cells,
thereby supporting the priming of the immune system so that subsequent exposure to
the antigen results in a rapid immune response (Fig.
18.2).
18.2 Current Vaccines Options
In their traditional organisation, vaccines are classified as live and non-live. This
classification allows us to distinguish between vaccines that contain attenuated
replicating strains of the pathogenic organism and those that contain only components of the pathogen. More recently, several other platforms have been developed
and many of these exploit nanoparticles to promote immune responses.
Live-attenuated vaccines are composed of microbial agents that have undergone
specific mutations, rendering them less capable of growing in human cells and no
longer pathogenic to humans. Although these microorganisms can still infect their
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Fig. 18.2 (a ) Examples of nanoparticles that can be used to improve the delivery of vaccines by (b)
promoting a primary response and acquired immunity such that when the immune system encounters the pathogen, it can quickly respond to infection. (Created with
BioRender.com)
target cells, the resulting infection is mild, and the replication of the microorganisms
is limited. Prominent examples of vaccines produced using this approach include the
Bacillus Calmette–Guérin (BCG) vaccine and the combined measles, mumps,
rubella, and yellow fever vaccine (MMR). Such vaccines are generally effective in
eliciting both humoral and cell-mediated immune responses. However, it is important to note that live-attenuated vaccines carry a potent
ial risk of reverting to
virulence. Therefore, their administration is not considered safe for immunocompromised individuals. Despite this limitation, these vaccines have proven to be
valuable tools for promoting immune protection against targeted diseases.
Killed whole or inactivated vaccines are composed of microorganisms or viruses
that have been rendered non-infectious through processes such as heat treatment or
chemical treatment with substances like formaldehyde. These methods effectively
eliminate their ability to cause infection while preserving their immunogenicity.
While these vaccines provide safety advantages, they generally exhibit lower efficacy compared to live-attenuated vaccines. They typically induce primarily humoral
immunity and often necessitate booster doses to maintain protection. Several examples of killed whole or inactivated vaccines include trivalent-inactivated influenza
vaccines, cholera vaccines, and hepatitis A vaccines.
Toxoid vaccines are produced by some microorganisms that produce toxic compounds responsible for causing the disease (i.e. tetanus toxin and diphtheria toxin).
Toxoids are inactivated forms of these toxic compounds. In addition to being
successful vaccines, toxoids may also be used to increase the immunogenicity of
some other vaccines, such as Haemophilus influenzae type B (Hib), which contains a
polysaccharide unit from the virus conjugated to diphtheria or tetanus toxins.
Subunit vaccines, which include purified proteins, recombinant proteins, poly-
saccharides, and synthetic peptides, can initiate strong immune responses when
combined with adjuvants. The main benefits of subunit vaccines are their inability
to revert to a pathogenic form, decreased toxicity, reproducible production, and
improved antigen specificity; however, the immune response induced by such
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vaccines is short-lived, and thus several boosts are required to achieve protection.
For the Hepatitis B virus, for example, only the surface protein of the virus is used to
generate the subunit vaccine.
Virus-like vesicles mimic the characteristics of viruses while lacking their genetic
material. They are derived from the outer membrane of cells, typically from bacteria
or mammalian cells, through various techniques such as cell disruption or membrane
blebbing. These vesicles can be engineered to display specific antigens on their
surface, triggering an immune response upon administration. The Group B meningococcal vaccine is an example of this type of vaccine.
Protein–polysaccharide conjugates represent a class of vaccines where polysaccharides from pathogenic microorganisms are chemically linked to carrier proteins. This conjugation process enhances the immunogenicity of the
polysaccharides, as they alone may not elicit a robust immune response. The carrier
protein serves as a scaffold, enabling the immune system to recognise, and mount a
stronger immune response against the attached polysaccharide. Examples of these
types of vaccines include Streptococcus pneumoniae and Haemophilus influenzae
type B vaccines.
Nucleic acid vaccines use either DNA or messenger RNA (mRNA) to deliver
genetic instructions to cells within the body. DNA vaccines contain a small, circular
piece of DNA encoding the antigen of interest, while mRNA vaccines carry a
synthesised mRNA sequence encoding the antigen. Once administered, the genetic
material is taken up by cells, which use it as a blueprint to produce the antigen
internally. This antigen production triggers an immune response, stimulating the
production of specific antibodies, and activating immune cells. Examples of mRNA
vaccines include the Pfizer-BioNTech and Moderna COVID-19 vaccines.
Recombinant viral vector vaccines use the replication machinery of viruses to
deliver and express specific antigens of interest. These vaccines employ harmless
viral vectors, engineered to carry and deliver genetic material encoding the desired
antigen into the cells of the vaccinated individual. The viral vectors, such as
adenoviruses or modified vaccinia viruses, have been modified to remove their
ability to cause disease while retaining their ability to efficiently infect cells and
produce the desired antigens. Once inside the host cells, the viral vec tors instruct the
cells to produce the antigen, triggering an immune response. Examples of these types
of vaccines include the Oxford-AstraZeneca SARS-CoV-2 vaccine.
Not all these options may be applicable for a given pathogen and Fig.
an overview of options for vaccine develo pment against a viral infection. In general,
live vaccines produce strong immune responses but may induce some mild disease
and may have the potential to replicate in an uncontrolled manner in immunocompromised individuals. In contrast, non-live vaccines do not present this risk; however
they often require an adjuvant to improve their ability to induce an immune response.
On several of these vaccine platforms, delivery systems and/or adjuvants are
required; DNA and RNA vaccines require a delivery system to protect the nucleic
acid payload, while peptide and sub-unit vaccine formulations need adjuvants to
improve immune response, and their mechanisms of inducing immune responses can
differ (Fig.
18.4). The mRNA vaccines are delivered to bystander cells inside lipid
18.3 gives
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Fig. 18.3 An overview of different platforms for viral vaccine development. Strategies include live
attenuated, inactivated, and use of synthetic peptides and recombinant approaches. (a) Live
attenuated, (b) whole inactivated, (c) split inactivated, (d) synthetic peptides, (e) virus-like particles,
(f) DNA or RNA, (g) recombinant subunits, (h) recombinant bacterial vectors, (i) recombinant viral
vectors. (Created with BioRender.com)
Fig. 18.4 Immune responses induced by nanoparticle-based vaccines. mRNA vaccines use lipid
nanoparticles to deliver modified antigen-coding mRNA to bystander cells at the injection site. The
translated antigen is then secreted, taken up, and processed by antigen-presenting cells (APCs). In
sub-unit protein-based vaccines, the protein antigen can be entrapped or associated with liposomes,
allowing direct processing by APCs. Virosomes, containing protein antigens on their surface
nanoparticles, are also directly processed by APCs. (Created with BioRender.com)
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