Oral Vaccines-Types, Delivery Strategies, Current and Future Perspectives
Abstract
Oral immunization is considered the most convenient route of
vaccination rather than any other route due to their abundance of
facilities over the traditional vaccines. Gaining of mucosal immunity
through oral vaccination can act as a protector against human to human
or animal to human pathogenic transmission of diseases and also inhibit
the pathogenic replication in the mucosal area which is the most
preferable able route of microbe’s penetration to the host blood
circulation. Unfortunately, there are a handful of oral licensed
vaccines in the market due to several drawbacks. Here, we tried to
present a brief discussion on the various type of vaccines, oral vaccine
delivering strategies and their current and future perspectives.
Abbreviations: OPV: Oral Polio Vaccine,
VAPP: Vaccine-Associated Paralytic Polio, HBsAg: Hepatitis B Surface
Antigen, HA: Hyaluronic Acid, HIV: Human Immunodeficiency Virus
Introduction
After the penetration of pathogenic microorganisms in our body, they
(germs) instantly start to invade and multiply to increase their
soldiers against body’s immunity system resulting infection. Even though
the immunity system has its own mechanisms to battle against such
harmful germs by using its macrophages, T-lymphocytes as well as
B-lymphocytes, maximum times fail in case of very harmful pathogens.
According to the statistics of WHO in the year 2016, infectious diseases
are still now causing severe mortality globally, especially in
developing countries whereas infections are responsible for more than
30% of total death among top ten causes of human mortality [1].
Nowadays, researchers are more likely tend to develop vaccines to combat
and eradicate deadly infectious diseases because of their extreme
capability to fight against pathogens along with immunity. Moreover,
vaccines have been used against various lethal infectious diseases from
1796 when Edward Jenner for the first time introduced smallpox vaccine
till now with success [2]. Vaccines are usually a type of biological
accumulation of antigens that take a step to activate adaptive immunity
by mimicking an infection, thus, vaccines obviate harmful microorganisms
as well as impede microbial evolution. The infection which is caused by
vaccines usually doesn’t cause illness of an individual, but his/her
body be aware of this infection by treating this vaccine a threat and
creates antibody and memory cells for further facing that infections
causing microbes [3]. Immunization
through vaccination is beneficial not only for vaccinated personnel but
also his/her surrounding society by producing herb immunity [4].
Surprisingly, about 90% of total pathogens cross thin and easily
vulnerable mucous membrane to invade cellular mechanisms via dealing
with digestive, pulmonary and genitourinary systems due to the big
surface area [5].
Hence, primary targeting site like a mucosal barrier for vaccine
delivery would be the appropriate decision against infection-causing
pathogens. Once first defensive line will be strong only a few pathogens
can cross the barrier. Researchers already proved that vaccine delivery
targeting mucus membrane can easily produce mucus antibody IgA against
pathogens [6] as well as increase cellular immune by secreting systemic
antibody IgG [7,8]. Thus, when one site of the mucosal barrier will be
protected, others site will be automatically protected through mucosal
inner safeguard network [9]. Through oral vaccine delivery, it is
possible to target the mucosal barrier rather than other routes of
administration because of oral delivery of vaccines facilitate both IgA
and IgG secretion in the body. Moreover, oral delivery is not the only
potential for the best protective mechanisms but also it has its other
merits like enhanced patient compliance, price-effectiveness,
large-scale production, no harm and infection from the needle and so
one. In contrast, IV/IM/SC administrated vaccines aren’t able to stop
pathogens in the mucosal barrier. Developing of oral vaccines is a novel
approach by considering their challenges like
extremely acidic condition, proteolytic enzymes, bile salts and their
pharmacokinetics (ADME). Unfortunately, most of the potential
vaccines are taken through injection whereas a handful number of
vaccines are available for oral administration [10].
Vaccine Types
Scientists are trying from the time remember to develop
various types of vaccines against harmful infectious pathogens
with a similar function to teach the immune system how to combat
against germs. For developing a vaccine against a specific virus
infection, it is more important to consider both how germs attack
the cells and how the response of our immune system to the germs.
As vaccines enhance our cellular immunity, it is considered as
the pre-treatment of pathogenic microorganisms before getting
disease-causing microbes. However, according to the formulation
and mechanism, vaccines can be categorized in the following folds.
Live Attenuated Vaccine: Among all types of vaccines, live
attenuated vaccines are considered as the most successful and
cost-effective [11]. Even, the history of vaccination was written
with smallpox vaccine which was live attenuated. In addition,
another attenuated vaccine such as the rabies vaccine was the first
human vaccine that was made in a laboratory [12]. Live attenuated
vaccine is usually developed by delivering the weakened virus to
the human body. The delivered live attenuated viruses can result
in asymptomatic infection without having a serious illness and
harming another individual by means of spreading, thus, increase
immune response and antibody production targeting to the specific
delivered virus. The mechanisms behind the live attenuated vaccines
why they usually don’t create serious illness is, before introducing
the selected live but weakened virus into the human body, they
(virus) passage through in cell culture or animal embryo about
200 times to reproduce themselves. Among them, low virulence
viruses are selected to grow in a large scale for preparation of a
vaccine. Viruses which are low virulence they can easily replicate in
a series of cell culture or in the chick embryo but not in the human
host. Because of those weakened viruses are used to reproduce
themselves in chick embryo or another media, hence, when they
just change their hostile environment they cannot replicate or
reproduce. Howsoever, the human body’s immune system certainly
attacks these weakened viruses by considering them as a threat
and produce antibody to fight against them as well as keep some
memory cells in the blood. In future, when same viruses come to
cause infection memory cell and previously produced antibody
catch and kill them [13].
Live attenuated vaccines facilitate lifetime safeguard against
the virus by taking only a single or highly two doses of inoculation.
These vaccines usually modulate all types of the immune signal
as cellular immune mechanisms against viruses by secreting both
IgA and IgG [14]. Not only that, live attenuated viruses confirm
heterologous effects which are very potential to save an individual
from non-specific infection [15]. Very rarely, attenuated viruses
can reproduce in the human host which is more dangerous, hence,
researchers should be concern about their responsibilities when
planning to develop an attenuated vaccine [16]. In addition, the
live attenuated vaccine is more likely cause adverse effects rather
than any other vaccines because of its weakened but live virus. In
a weak individual whose immunity system is not so strong like
cancer or HIV patients to handle weakened live viruses, there are
more possibilities of replication of viruses in the human body and
cause infections [17]. For example, in the United States attenuated
oral polio vaccine (OPV) is prohibited since 2000 according to the
evidence of vaccine-associated paralytic polio (VAPP). National
vaccination policy ruled the use of inactivated polio vaccine instead
of OPV in 1997 when they found 9 persons were infected every year
due to the administration of OPV [18].
Killed-Whole Cell Vaccines: To overcome various drawbacks
of attenuated vaccines, killed-whole cell vaccines aroused which are
known as inactivated vaccines. To produce an inactivated vaccine,
researchers usually banish the targeted virus or bacteria and let
them reproduce in culture. After that, those viruses are inactivated
by heat, radiation or using chemicals like formalin or formaldehyde.
Next, inactivated viruses are reproduced in large scale for
preparation vaccine. Inactivated vaccines are more protective and
static in comparison with the attenuated vaccine. In fact, whole
killed vaccines cannot cause infections though it elicits a less strong
immune response than live attenuated vaccines. The mechanism
of actions behind their unique properties is when viruses or
bacteria are inactivated in the laboratory they cannot replicate or
reproduce within the human body (killed whole bacterial or viral
organisms). In such conditions, though viral or bacterial organisms
are inactivated they are intake this is because our body’s immune
system can easily recognize them and take further protective steps
against such bacteria or viruses. Moreover, inactivated vaccines can
be stored at the freeze-dried form and no need for refrigerating,
so, in underdeveloped countries where need vaccination they can
easily get it. Though inactivated vaccines are more safe with fewer
side effects than attenuated vaccines, killed-whole cell vaccines
exhibit less immune responses as well as antibodies. In addition,
additional dose like booster doses is required to boost immune
systems for long-term immunity in the case of inactivated vaccines
[19].
Sub-Unit Vaccines: Unlike traditional live attenuated and/or
inactivated vaccines in which live or inactivated germs were used,
subunit vaccines contain the only antigen of a specific pathogen
where there is no chance to get back as mutant [20]. Sometimes,
the only epitope of antigens is used as a vaccine in which paratope
(antigen-binding portion) of an antibody bind. In a subunit vaccine,
1to20 antigenic part of microbes can be used which are more
potential to exhibit a strong immune response [21]. To develop
such efficacious, safer and more cost-effective vaccines with great
pharmacological stability and to find out which combination of
subunits provide strong immune responses, scientists test antigens
of various potential subunit-like protein, sugar, and capsid. As only
fragments of microbes are present in this type of vaccines, body’s
immunity system can attach to the key part of bacteria or viruses
and finally destroy that’s why every individual who has strong
or less immunity can take this vaccine [22]. Though it provides
strong immunity, additional booster doses are required to continue
to prolong immunity. One of the major downsides of this vaccine
is, no confirmation regarding forming immune memory cells. In
comparison with live attenuated vaccines, they are less strong by
means of immune responses [23]. Subunit vaccines can be further
divided into the following categories.
Protein-based Subunit Vaccines: Protein-based vaccines are
a type of subunit vaccines in which disease-causing proteins by
means of antigen are used as a therapeutic tool. For developing
such kind of vaccines researchers usually grow the bacteria or
viruses in cell culture and then disintegrate those bacteria or
viruses via using chemicals. Next, targeted proteins are collected for
preparing vaccines. The proteins are isolated and purified before
use as vaccines. Proteins are fragile in nature. Hence, there is more
possibility to degrade by different pH factors of the gastrointestinal
tract and/or to denature by proteolytic enzymes like trypsin,
chymotrypsin, and pepsin. These brittle proteins have a various 3D
structure that’s why immune’s antibody does not recognize them
easily; resulting in non-specific antibody binding.
Polysaccharide Vaccines: In polysaccharides vaccines, a part
of pathogenic polysaccharide capsule or pure cell membrane of
sugar coat for example surface protein of polysaccharide is used.
Sometimes bacterial or viral disease causing antigens are protected
by their own sugar coat generally known as polysaccharides from
body’s natural defensive mechanisms [24]. This mechanism gives
researchers two key points, first, develop such type of vaccines by
which specific antibody can attach to the molecules in bacterial or
viral polysaccharide capsules, second, bacterial protein is coated
with the polysaccharide that’s why infants and young children’s
immunity’s system cannot recognize them. This is maybe for the
improper development of the baby’s immune system. However,
the poor immunogenicity of children to polysaccharide vaccines
downregulate their usages in the western or developed countries
[25]. Though it is very easy to prepare anti-capsular antibody
polysaccharide vaccine, it is used only for short time defensive
mechanisms. As antibody generation is very slow with these
vaccines, immunogenicity is also very poor, even, poor immune
memory [26].
Conjugates Vaccine: The underdeveloped immune function of
children that cannot work against polysaccharide antigens and the
differences between mature and immature immune systems are
one of the main causes to develop conjugate vaccines. The modern
technology chemically linked a protein carrier (diphtheria or tetanus
toxoids) from a different agent with microbial polysaccharide cell
wall to enhance immunogenicity for a long time even in children
[27]. The chemical linkage is the main reason why polysaccharideprotein
conjugation vaccines are better rather than polysaccharide
vaccines. Due to the introduction of the protein carrier with
polysaccharide cell wall of microbes, an immature immune system
can detect the polysaccharide coatings and immediately react to the
bacterium [28]. To be specific, T cells of our immune system (both
adult and child) first detect the protein carriers of polysaccharideprotein
conjugation vaccines as well as alert B cells about the
entrance of pathogenic antigens as foreign materials in our body.
Then, plasma B cells produce a huge amount of antibody to destroy
such threats [29]. The remaining memory B cells act as a defensive
soldier against the microbes in future.
Toxoid Vaccines: Few bacteria like Clostridium tetani and
Corynebacterium diphtheriae secret their poison called toxin in the
bloodstream that can cause serious illness with severe symptoms.
Inoculation against these bacteria is started base on their produced
toxins. Scientists detoxified (inactivated) bacterial toxins by using
formaldehyde solution with double distilled water or sometimes
by heat or radiation. Finally, those inactivated toxins (toxoids)
are used as vaccines. When bacterial toxoid is introduced in the
human body, the natural immune system learns how to fight actual
bacterial toxin [30]. Bacterial inactivated antigens (toxoids) are
naturally innocuous because detoxified toxins cannot back at its
virulent for even cannot multiply within the human host. Besides,
toxoid vaccines are cost-effective, permanent and not prehensile
to warm and damp [31]. Calcium and aluminum salts are used in
the preparation of these vaccines to increase and strengthen their
immune activity [27].
Oral Vaccine Delivering Strategies
There is no doubt that oral vaccine delivery is the most likely
route among all routes of administration. Despite it, researchers
usually concern about various physiological barriers and
conditions of the human body and their interactions with vaccine
therapeutics. For examples, vaccines particles first face the extreme
acidic conditions of GIT as the first barrier, later on, the intestinal
barriers like differences proteolytic enzymes (chymotrypsin,
trypsin, bromelain, pain etc.), mucin barriers, intestinal retention
and absorption of therapeutic particles also impede the successful
oral vaccines delivery. In addition, generation of prolonging
immunogenicity both in mucosal surface and systemic blood
circulation depends on not only the successful oral delivery of
vaccines but also their half-lives [32]. For low delivery strategies of
vaccinogens by the oral route, high concentration or rapid delivery
of vaccines particles are needed in comparison with other routes
[33]. To overcome such drawbacks, researchers already proposed
various oral delivery techniques as described below
Bacterial and/or Viral Vectors: In the promising field of
recombinant biotechnology, using live vectors as either bacterial
or viral are considered one of the most successful strategies in the
account of oral vaccine delivery. Bacterial or viral vectors can cause
upward trends of T-cell as well as mucosal and circular antibody
promptness. Furthermore, immunogenicity works against both the
antigens and their carrier by means of live vectors such as a double
vaccine. Bacterial and viral vectors can replicate itself in the host,
that’s why more immunity produce against those vectors. Thus,
these types of adenoviral systems can introduce a repetitive and
sufficient amount of antigens to the internal immunity of the host.
Nowadays, a series of live attenuated microbes are widely used for
delivering of disease-causing antigens. For proposing a potential oral
delivering strategy regarding the adenoviral system, researchers
should diligently take into account the safety profile of live vectors
due to their enhancing chances of causing virulence. An example
would be, the use of Streptococcus pneumoniae as a bacterial
vector for those who have the previous history of pneumonia. Not
only that, live vectors are unable to protect vaccinogens in the
1.2 pH of the stomach. Alginate coating of live vectors would be a
suggestion for this unwanted situation. Target delivery of vaccine
therapeutics with live vectors also possible through polymerization
of vectors. Bacterial vectors recently used as an effective carrier of
DNA vaccines facilitating enhanced physicochemical stability and
prolonged immunity which will be very cost-effective [34].
On the other hand, S. typhi was successfully used as vector
against hepatitis B diseases to deliver recombinant hepatitis B
virus surface antigen in mice model [35] but no adequate response
regarding immunogenicity was found in human [36]. In the second
last decades, Tacket CO, et, al., proved that S. typhi can enhance
serum antibody level against tetanus toxin (fragment C) [37]. Like
recombinant bacterial vectors, a series of viral vectors are also using
targeting various diseases. Among them, the adenoviral vectors are
notably used worldwide. In the year 1979, Takafuji et al., described
that live adenovirus can be used against respiratory tract infections
[38]. Adenoviral based oral vaccine delivery is not only effective
for human but also for veterinary used [39]. Unfortunately, in
phase 1 clinical trial, one dose of hepatitis B vaccination to healthy
individuals did not found any hepatitis B antigen-specific antibody
response [40]. Though live vectors can replicate in the intestine,
enhance antigen absorption as well as target M cell in the follicleassociated
epithelium of the Peyer patch, researchers suggest to the
enteric coat of adenoviral vectors for preventing them from harsh
gastric juice [41]. There is also another two type of viruses that are
used as live viral vectors known as vaccinia and polioviruses [42]
though using poliovirus as live vectors have their own limitation
too.
Transgenic Plants: Traditionally plants are being used as
therapeutics for thousands of years targeting various diseases [43-
45]. From many years, researchers were more tending to discover
plant-based vaccine producing and delivering strategies. Now,
various plants are used as transgenic plants facilitating needlefree
oral vaccination to both infants and adults. Transgenic plantbased
oral vaccine delivery facilitates a lot of advantages like
locally cost-effective production, no need to use the refrigerator
for storage and according to the statistics, the antigens present
in the plant’s parts like seeds or leaf are stable even in room
temperature [46]. Transgenic plant-based inoculation can able
to ensure mass vaccination which is very important for different
developing countries. Early studies of transgenic plant-based
vaccine production and delivery especially emphasized on potato
and tobacco plants targeting various life-threatening diseases, for
example, hepatitis B, malaria, HIV, and so ones. Among them, the
Hepatitis B virus vaccine through transgenic plants achieved the
most successful rate. An example would be, Mason SH et al., used
tobacco leaves for the large-scale production of hepatitis b surface
antigen (HBsAg) is almost similar to human serum’s HBsAg [47].
They also proved that no obstacle would arrive regarding
normal transcription or translation of antigen in transgenic plants
like a tobacco plant. Another research suggested that regulating
the expression of HBsAg using leaves of Nicotiana tabacum plant
is also possible [48]. In this research article, Kumar GBS, et al., for
the first time claimed about the expression of HBsAg in tobacco
seeds. In addition, Richter and co-workers studied the ability of
serum antibody production of transgenic potato plant derived
antigen in a mice model as the preclinical studies that indicated a
successive preliminary immunogenic response against delivered
antigen [49]. Some researchers just took a gene responsible for
Hepatitis B and inserted the gene into potato for developing a new
era in vaccinology especially for poor countries [50]. Nevertheless,
rice and corn also took an interest in oral vaccine delivery because
these foods are used as baby food rather than any other food
[51,52]. Vaccination with transgenic plant-derived antigen is more
acceptable and reliable rather than any other sources.
Lipid-based Vectors: Liposome contains lipid bilayer systems
in which they can imbibe both hydrophilic nucleic acid, vaccine’s
antigen, and hydrophobic drugs at a time. Through surface
modification, they can facilitate target delivery of antigen to m-cell
and protect antigen from extreme physiological pH. Modified
liposomal systems with vaccinogens, adjuvants, and targeting
moiety are increased oral vaccinology even though they have
limited conduction to gut-assisted lymphoid tissue and systemic
absorption. From the starting history when Childers and colleagues
proved liposome-based secreting IgA secretion [53], after that, a
lot of data indicated their ability to enhance mucosal immunity like
Chaicumpa et al., compared the liposomal-based cholera antigenmediated
immunogenicity with naked antigen resulting in a novel
approach of oral cholera vaccine delivery via the liposomal system
[54]. Fortunately, lipid-based vectors have more interaction ability
with intestinal m cells which is the key transporting components of
oral vaccine delivery in comparison with any other cell like mucussecreting
goblet cell or other enterocytes. M cells are responsible for
both receptor-mediated or non-receptor mediated transportation
of liposome vehicles [55,56]. The introduction of the liposomal
system in oral vaccine delivery from the end of the last decades
presented various animal studies as well as clinical data but their
superabundant vaccination effects are still in major questions.
Nanoparticle-based Transportation: Oral vaccine delivery
using nanoparticles are usually considered the most successful
strategy among all transportation systems. Nanoparticles are
usually biocompatible and biodegradable in nature that can
protect vaccinogens from acidic ph and enzymatic degradation.
Nanoparticles like Betaglucan itself has the ability to target M cell. In
addition, surface-modified nanoparticles with GRGDS or CKS9 like
M cell targeting moiety can able to target wise delivery of antigens
into M-cell [24]. On the other hand, positively charge nanoparticles
can easily target negatively charged M cell. Thus, targeting ability of
nanoparticles based vaccine delivery system is the most convenient
than any other systems. To be specific PLG, PLGA, PEG and PELA are
the common polymeric nanoparticles for vaccine delivery.
Denaturation of these nanoparticles by various physiological
enzymes may decrease their potentiality. Protamine is another
impressive nanoparticle that can conjugate with antigen through
electrostatic interactions and also protamine either alone or in
combination with antigen can be localized into nuclease. Watersoluble
chitosan and HA (hyaluronic acid) are another novel
postulant under this system. Thousands of studies suggested their
acceptability in oral vaccine delivery. Hence, nanoparticle-based
transportation of viral antigen for convenient oral delivery would
be the best answer to those arising questions related to major
obstacles of oral vaccine delivery strategy. There are also a few
of strategies like immune stimulating complexes and virus-like
particles which also influence researchers to develop a new oral
vaccine to overcome traditional vaccine strategies.
Progression of Oral Vaccines
Oral vaccines have been developed emergingly from the first
application till now. Several oral vaccines are available in the market
and a few are in clinical trials. A list of oral vaccines progression is
given here for research perusal [1,27,42,56,57] (Tables 1 & 2).
Conclusion and Future Perspectives
Vaccine delivery techniques have improved a lot with the pace
of time even though there are a few vaccines available in the market
so far. Oral vaccine delivery is most convenient for the patience
and higher efficiency of vaccines can be achieved by oral gavage
compare to other delivery routes. So far, oral vaccines are delivered,
targeting the M-Cells in small intestine due to better uptake
performance. But number of M-cells are very few in the human
body, thus it is important to find another mechanism to delivery oral
vaccine successfully. In future, researchers might target other cells
rather than M-cells and there is ongoing work based on targeting
epithelial cells and so on. Several oral vaccines, e.g., hepatitis C, HIV
(Human Immunodeficiency Virus) are on Phase II trials and can
bring success in oral delivery vaccines in future.
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