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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5577_Библиотеки_им_академика_М_И_Перельмана.pdf
Vaccine class
Novel Nucleic-
acid
— Viral-vectors Non-pathogenic
Vac cine
type [31] Composition
Outer
Membrane
Vesicles
Bacterial outer
cell membrane
component
(OMVs)
Virus-like
Particles
(VLPs)
Non-infectious par-
ticles mimicking
viral structure
mRNA mRNA encoding a
specific bacterial/
viral protein
DNA DNA encoding a
specific bacterial/
viral protein
viruses with
genes encoding
specific viral/bacterial antigen
Table 1: (Continued)
Bexsero®
vaccine
Heptavax
vaccine
Gardasil®
vaccine
Comirnaty
vaccine
Anthrax
vaccine*
Ervebo
vaccine
Vaxz evri a
vaccine
Meningococcal
disease
®
Hepatitis B Hepatitis B
Cervical cancer
& warts
®
COVID-19 SARS-CoV-2 [53] 2020 –
Anthrax Bacillus
®
Ebola Zaire
®
COVID-19 SARS-CoV-2 [58]
Vaccine example
Neisseria
meningitidis
(Serotype B)
virus
Human
Papilloma
Virus (HPV)
anthracis
ebolavirus
First
licensed in:Name Disease Pathogen Reference
[4 9] 1987 –
Meningococcal B
(MenVBac) [50]
[51] 1986 –
Hepatitis B [52]
COVID-19
Comirnaty®
vaccine [54]
[55] *None licensed for
use as of 2021
[56 ] 2019 – Ebola [57]
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Novel and Traditional Vaccines
Traditional vaccines
Traditional vaccines were the earliest developed vaccines [59]. Generally, they contain whole pathogens or pathogenic sub-units [60]
which are directly recognized by the body’s immune cells [61, 62].
Whole pathogen vaccines are the oldest vaccines with many studies supporting their ecacy [63–65], and they may be further classified into live attenuated or inactivated vaccines. Live attenuated
vaccines contain modified whole bacteria or viruses with decreased
virulence, sucient to induce an immune response but not cause
disease. Such vaccines are occasionally unsuitable for immunocompromised patients due to the risk of reversion to its virulent state
[66] and in such cases, inactivated vaccines may be used instead.
Inactivated vaccines contain whole bacteria or viruses that have
been chemically or heat-killed and are hence unable to replicate.
One example of such vaccine often used for children is the Inactivated Polio Vaccine (IPV) administered to pre-school children.
323
Another class of traditional vaccines comprises subunit vaccines
which are acellular. The recombinant vaccines consist of bacterial or
viral protein fragments as the antigen for immune cell recognition
[67]. Bacterial toxins are also used in vaccines, but they are often
inactivated to form toxoids that can trigger an immune response
without causing disease. Vaccines using such toxoids are known as
toxoid vaccines. Studies have shown that some bacterial polysaccharides used in vaccines are more ecacious in inducing an immune
response when conjugated to proteins such as diphtheria or tetanus toxoid proteins due to the toxoid’s high anity for immune
cell recognition. Hence, conjugate vaccines such as the Hemophilus-
Influenzae type b vaccine, containing polysaccharides conjugated to
the tetanus toxoid, have been developed as well.
324
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Apart from toxoids, newer technology allows a non-infectious component of bacterial outer cell membrane known as outer membrane
vesicle (OMV) to be used as an antigen in OMV vaccines. An example of a licensed OMV vaccine is the Bexsero
®
vaccine used in the
United States against the Type B meningococcal virus which causes
meningitis and sepsis [68]. Another newer traditional vaccine is
the VLP vaccine which contain naturally occurring or chemically
synthesized virus-like particles (VLPs) as the antigen of interest. In
fact, VLP vaccines can also be manufactured with dierent antigens
from multiple pathogens incorporated together.
While vaccines can be separated into the above-mentioned classes
according to their characteristics, distinct classification is occasionally impractical such as in the case of combination vaccines. One
combination vaccine is the Infanrix Hexa
®
6-in-1 vaccine used in
the United Kingdom [69] containing both inactivated viruses and
recombinant viral proteins. The single combination traditional vaccine oers protection against 6 diseases, namely diphtheria, tetanus, pertussis, polio, influenza B and hepatitis B [70].
Novel vaccines
Traditional approaches to conferring immunity may be ineective
for chronic or newer infections that require more specific focus on
certain antigens [71]. Hence, new methods of delivering pathogenic
antigens have been developed. Novel vaccines are a recent development and they rely on pathogenic nucleic material or other alternative vector delivery systems instead of the specified pathogen [72].
The most well-known novel vaccines are nucleic acid-based vaccines
that use genetic material of the pathogen, such as mRNA and DNA,
Novel and Traditional Vaccines
to elicit an immune response [60, 73]. mRNA vaccines contain lipid
enveloped mRNA of the pathogen that are ultimately translated
by human cells to produce pathogenic proteins that act as immune
cell antigens. The Pfizer-BioNTech
®
and Moderna® vaccines against
COVID-19 are the two most recent examples. DNA vaccines contain bacterial or viral DNA, which do not require the protection of
any lipid membranes due to its higher stability relative to mRNA.
The pathogenic DNA undergoes additional transcription to mRNA
before embarking on a pathway similar to mRNA [74].
Live attenuated vaccines are the most widely used traditional vaccines due to the better-established balance between their immune
eect and safety [61]. They are also relatively long lasting [75]. On
the other hand, mRNA vaccines make up the biggest group of novel
vaccines to date [76], having undergone the most extensive research
and development among the novel vaccines [77, 78]. For simplicity,
this review will focus on live attenuated vaccines and mRNA vaccines as examples of traditional and novel vaccines respectively.
325
Vaccine manufacture
The manufacture of vaccines is an elaborate process chain involving
many well-coordinated steps [79]. Depending on the composition of
a vaccine, the complexity of the steps may dier. It is also more complex to manufacture combined vaccines, e.g. MMR vaccine, than
single vaccines. Figure 1 shows the dierent levels of complexity in
the manufacture of dierent types of traditional vaccines.
Depending on the type of traditional vaccines, the complexity and
need for additional steps will vary. However, traditional production
326
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Polio Tetanus Pertussis Influenza Hep B Pertussis MMR Pertussis
Vaccine Vaccine Vaccine Vaccine Vaccine Vaccine Vaccine Vaccine
Class Live attenuated Toxoid Inactivated Inactivated Recombinant Sub-unit Live attenuated Conjugate
Type Viral Bacterial Bacterial Viral Viral Bacterial Viral Bacterial
Increasing complexity of manufacture process
Figure 1: Complexity in the manufacture of dierent types of traditional
vaccines [80]
Hep B: Hepatitis B; MMR: measles, mumps, and rubella.
vaccines tend to have relatively less complicated steps compared
to novel vaccines which require a more precise coordination of
steps. However, there are general manufacturing steps that are common to most vaccines, both traditional and novel, as summarised in
Figure 2.
The first step in the manufacture of traditional vaccines is to generate the antigen used to stimulate antibody production. This antigen is specific to each vaccine and will require specific conditions.
Most traditional vaccines require the growth of a pathogen, such as
viruses or bacteria, as the antigen. These pathogens are commonly
grown in various cell cultures. Eggs and mammalian cells are most
commonly used for viruses. The candidate vaccine virus is injected
into these eggs/cells that are later incubated to allow virus replication. Some methods use a chemical bioreactor to provide a favorable
environment for growth of bacteria. The manufacture of novel vaccines vary significantly as replication of pathogenic genetic material
is required instead.
Generation of
antigen/mRNA/DNA
viral-vector
Isolation of
antigen/mRNA/DNA
viral-vector
Purification of
antigen/mRNA/DNA
viral-vector
Formulation of
vaccine
Filling, packaging
and labelling
Novel and Traditional Vaccines
327
Inspection and
quality testing
Figure 2: General process flow of vaccine manufacture [81]
For mRNA or DNA vaccines, replication of pathogenic DNA is the
first step of its manufacture. The biosynthesis of DNA begins when
plasmids containing specific viral DNA are inserted into bacterial
cells such as Escherichia coli (E. coli), and these genetically-modified bacteria are allowed to replicate in bioreactors. For mRNA vaccines, additional transcription of the DNA to mRNA is completed
using specific enzymes and chemicals. Novel vaccines using viral
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
vectors will require an additional step as the DNA plasmid will
need to be inserted into non-pathogenic vector viral cells before
replication.
In traditional vaccines manufacture, the resultant antigen has to
be isolated from the culture medium and purified. For most vaccines, this begins with the separation of the pathogen from its cell
culture medium. From here, each vaccine type will require specific
additional steps. Live attenuated vaccines will require reduction in
the pathogen’s virulence through multiple sequential cell cultures
or chemical processes to decrease virulence [79]. One example is the
Bacillus Calmette-Guerin (BCG) vaccine, where live strains of the
bacterium, namely, Mycobacterium bovis (M. bovis) [82] are weakened
and used to confer immunity against tuberculosis [83]. The pathogens used in inactivated vaccines undergo inactivation by heat [84],
chemicals like hydrogen peroxide [85] or ultraviolet (UV) radiation
[86]. Subunit vaccines will require physical disruption of whole
pathogens to obtain the specific antigens needed, such as viral proteins or bacterial toxins.
Thereafter, the isolated antigens undergo multiple purification
steps, including filtration, chromatography, clarification and concentration [87]. Simple purification methods exploit particle size
dierence, where hollow fibers or flat screens are used to filter out
antigens of a specific size. The liquid containing the antigens can be
flushed in a direction parallel to the filter, known as tangential flow
filtration, to ensure continuous filtration and better recovery of the
antigens. When the size dierence between contaminants and antigens are significantly less distinct, high anity chromatography is
a common method of purification [88]. The antigens and other components are separated based on their ionic charges or hydrophobic
Novel and Traditional Vaccines
interactions instead. For nucleic-acid based novel vaccines, DNA and
mRNA have to be isolated and purified.
After purification, the next step is to formulate the vaccine by incorporating the relevant components [89]. Antigens may be combined
with an adjuvant to intensify the immune response triggered [90].
Stabilizers, such as surfactants [91], are added to extend the shelf
life of vaccines. Some multi-dose vaccine formulations include preservatives to prevent unwanted microbial contamination [92]. All
the above-mentioned steps are normally carried out in a segregated
cleanroom of the manufacturing facility as an aseptic environment
is required to prevent unwanted microbial contamination.
Finally, the manufactured vaccines are filled into sterile depyrogenated vials in an aseptic environment. The freshly manufactured
vaccines are sealed with sterile stoppers together with an outer cap
to enhance the physical protection against contamination. After
filling, the vials are clearly labelled. Upon completion, the sealed,
labelled vaccine vials will undergo strict testing and inspection
using specialized equipment to ensure container-closure integrity
and to eliminate any defects that may compromise the vaccine’s
quality. Throughout the entire manufacturing process, the raw
materials and products are to be kept strictly at their respective
optimal temperatures.
329
Vaccine storage, transport and distribution
Once manufactured, the vaccines are stored within the manufacturing facility at their recommended temperature until they are
ready for distribution. The storage, transport and distribution of
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
vaccines are constantly managed under temperature-regulated
environments. This is because high temperature can cause denaturation of the vaccine antigen and adjuvants. Hence, post-manufacture handling of vaccines involves a collective and continuous monitoring programme known as the vaccine cold-chain management
[93] as all vaccines are cold chain products (CCP). The management
of CCPs require high quality temperature control within a stringent temperature range, commonly at 2°C–8°C for most traditional
vaccines [94]. Some traditional vaccines, such as the hepatitis B vaccine and diphtheria vaccine, are prone to freeze damage [95, 96].
Under freezing temperature, the vaccines experience potency loss.
Administration of such freeze-damaged vaccines can result in an
increased risk of adverse eects such as sterile abscesses [97]. On the
other hand, novel vaccines, especially nucleic acid-based vaccines,
need to be stored at sub-zero temperatures in order to maintain
their potency. The mRNA or DNA in such vaccines are highly susceptible to enzymatic damage and hence ultra-low temperatures
are necessary to minimize enzymatic activity and any genetic material damage. Hence, vaccines have to be kept within the appropriate temperature ranges that are specific to the individual vaccines.
Table 2 summarizes some optimal temperatures of the dierent
types of vaccines.
The actual storage temperature of a vaccine will vary as it travels
from the manufacturing facility to the destination country and
vaccination center. The Pfizer-BioNTech COVID-19 vaccine may be
stored long term in ultracold freezers at a temperature of between
–90°C and –60°C. The vaccines arrive at the warehouses of destination countries in thermal shippers packed with dry ice, see Figure 3.
These thermal shippers maintain the vaccines at the required ultracold temperature of between –90°C and –60°C. At the destination
country, the temperature monitoring device in the thermal shipper
Novel and Traditional Vaccines
Table 2: Optimal storage temperatures of some vaccines
Vaccine name
BCG vaccine 2°C–8°C
Hepatitis Recombinant Vaccine 2°C–8°C
Inactivated polio vaccine 2°C–8°C
HPV Gardasil vaccine 2°C–8°C
Inactivated influenza vaccine 2°C–8°C
Rotavirus vaccine 2°C–8°C
MMR vaccine –50°C to –8°C
Varicella vaccine –50°C to –15°C
BCG: Bacillus Calmette–Guérin; HPV; Human Papillomavirus;
MMR: measles, mumps, and rubella.
Optimal storage temperature
331
Figure 3: Thermal shipper
is checked to assure that there are no temperature excursions during transportation.
The vaccines are transferred to higher temperatures in a step-wise
manner before use. Before mixing with the diluent for administration, the vaccine may be stored in a pharmaceutical refrigerator
between 2°C and 8°C for up to 1 month (31 days). Upon mixing
with the diluent (sterile saline), the reconstituted vaccines can be