Iris Publishers - Current Trends in Clinical & Medical Sciences (CTCMS)
Vaccination Contribution to World Health: History, Current and Future
Authored by Ebtsam M Es Kadys
Introduction
Stimulating and activating the
immune system against infectious diseases, by selecting vaccines in order to
prepare the immune system, and this stimulation is called immune responses,
which in turn provide acquired immunity to the disease against which the vaccine
has been immunized, which usually consists of the microbe or its derivatives
after weakening or destroying it. Vaccines may be prophylactic (to prevent or
mitigate the effects of a potential infection by a natural or wild pathogen) or
preventive (e.g. cancer vaccines under investigation) [1].
The inventions of Edward Jenner,
which began with his popular 1796 [2] by using cowpox material to establish
immunity to smallpox, rapidly spread the disease. At the beginning of the 19th
century, Jenner’s vaccine technique spread rapidly across the world, sponsored
by preferred governments to a measure that could minimize the devastating
effects of epidemics on their populations [3]. During the next 200 years, his
process underwent scientific and technological changes and eventually led to
the eradication of smallpox.
The development of vaccines has
increased significantly since the middle of the twentieth century, including
the manufacture of virus vaccines in terms of development and innovations such
as the polio vaccine and the triple vaccine (measles - German measles -
parotid). This development was done by DNA and it is considered one of the most
recent applications in the production and development of vaccines.
Main text
The different vaccine industry
depends on the method of combating disease-causing germs and viruses by
stimulating and stimulating the immune system. The response depends on the
technology and approach of the vaccine, as there are four groups in the vaccine
industry which are: polysaccharide, and conjugate vaccines. Subunit,
recombinant, Live-attenuated vaccines, Inactivate vaccines.
Live-attenuated vaccines: In this
type of vaccine, the microbe that causes the disease is used after it is
weakened or destroyed, and this vaccine is given an effective and long-term
immune response, and this immune protection is done by using one or two doses
of this type of vaccine. Live vaccines are used to protect against: measles,
mumps, rubella, rotavirus, smallpox, chickenpox, and yellow fever.
Inactivated vaccines: This type of
vaccine does not provide good immunity like live vaccines, and this leads to
the need for multiple doses of vaccination to obtain continuous immunity
against the disease and among these diseases are hepatitis, influenza, polio
and rabies.
Subunit, recombinant,
polysaccharide, and conjugate vaccines: These types of vaccines use only part
of the microbe, such as protein, sugars or capsid, as they target the main
parts of the microbe which leads to a strong immune response. One of the
negative aspects of this type is the need for multiple doses of the vaccine
which use for immunized against Hepatitis B, Whooping cough, Shingles,
Haemophilus influenzae type b disease, Human papillomavirus,, Pneumococcal
disease, and Meningococcal disease.
Toxoid vaccines: Toxoid vaccines
through converting the toxin into an toxoid in order to get rid of the toxicity
of the vaccine, As the toxoid affects the immune part of the microbe and not
the microbe itself which leads to the need for many doses (booster doses) of
the vaccine in order to obtain permanent or continues protection. Toxoid
vaccines are used to guard against: tetanus and diphtheria, diphtheria toxoid
occur by cross linked the A-B fragments of diphtheria toxin.
Emerging outbreaks of toxigenic
cutaneous diphtheria associated with conflict and failing healthcare systems:
The crisis threatens to devastate the world’s health-care system with
significant morbidity and mortality implications. While emergency immunization
programs are vital measures in the current situation to monitor and prevent
outbreaks of infectious diseases in the long term. Diphtheria is also an issue
with inadequate immunization coverage in a number of low-income countries.
Several outbreaks in Sub-Saharan Africa were recorded e.g. Nigeria and
Madagascar since 2000 [4]. Recently in South-East Asia the diphtheria outbreaks
such as the 2012-2013 People’s Democratic Republic of Lao [5] and 2015 and 2016
in India [6]. In 2017 there was a diphtheria outbreak among the Pemon ethnic
group Amerindians in Wonken, Venezuela [7]. Last but not least, the recent
ongoing diphtheria outbreak in Yemen2019 exposed the increasing number of cases
of diphtheria and deaths as well as the recent shortages of antitoxin
diphtheria and cases leading to immunization coverage failure [8]. WHO European
region reported the shortages of diphtheria antitoxin, the Strategic Advisory
Group of Experts (SAGE) on immunization called for a review of the evidence
available and the need to reexamine the current recommendation. Now let’s get
to know about this illness, its causes, symptoms and ways of defending us
against it.
Diphtheria
It is a serious bacterial
infection caused by the bacteria Corynebacterium diphtheria [Figure1].
Diphtheria causes the back of the throat to have thick covering. This can lead
to breathing difficulties, heart failure, paralysis and even death. The average
diphtheria case-fatality is 5-10 percent. Corynebacterium diphtheria has 4
subspecies (gravis, mitis, belfanti and intermedius). One of the most common
dangers of diphtheria is respiratory infection, and it also affects the pharynx
and tonsils. In severe cases, pseudo-obstructive membranes form in the
respiratory system, and complications of diphtheria are myocarditis and
neuritis. Diphtheria may occur in a cutaneous form, resulting in indolent skin
infection.
Diphtheria toxin: It is an
exotoxin which is secreted by the pathogenic causing diphtheria Corynebacterium
diphtheriae. A prophage (a virus that has itself inserted into the host
bacterium’s genome) encodes the toxin gene. It is responsible for the
Diphtheria symptoms. By 1888 the poison was isolated, in the year 1923 a
vaccine was made. Diphtheria toxin (DT) contains three structural domains, each
with a distinct biological function involved in cell poisoning: cell-surface
binding and internalization into endosomes, crossing of the endosome membrane
into the cytosol, and preventing the synthesis of cell proteins.
Pathogenicity of Diphtheria Toxin:
Diphtheria toxin is a protein that contains 535 residual amino acids. It is
synthesized as a single polypeptide, but it is proteolyzed in its active form
to two polypeptide chains connected by a disulfide bond. The fragment C-terminal
B (345 residues) contains the transmembrane and receptor binding domains, and
the fragment N-terminal A (190 residues) contains the catalytic domain [Figure
2]. On the cell surface, diphtheria toxin binds to the precursor of the
heparinbinding epidermal growth factor, and the complex of toxin-receptors
undergoes endocytosis mediated by receptors. Next, the A fragment is
translocated into the cytosol across the endocytic membrane. The catalytic
domain, once in the cytosol, catalyzes the transition of adenosine diphosphate
(ADP) ribose from nicotinamide adenine dinucleotide (NAD) to elongation factor
2, inhibits protein synthesis and results in cell death [9].
Nature and Pathogenicity of
Microorganisms: Diphtheria toxin is a part of the so-called bifunctional toxins
A–B. Fragmentart A is the enzyme activity responsible for halting protein
synthesis in the target cell, while Fragment B is related to the cell receptor
as it prevents the transfer of Fragment A into the cytosol Portion B accounts
for the cell and species specificity of the A–B toxins. Fragment B of
diphtheria toxin deals with a heparin-binding precursor of epidermal growth
factor, which is an essential hormone for cell growth and differentiation.
Uptake of diphtheria toxin is done through endocytosis mediated by the
receptor. Endocytic vesicle acidification induces a conformation of the
enclosed holotoxin, allowing Fragment A subunit of the diphtheria toxin to
traverse the membrane and reach its cytoplasmic target. The A subunit of
diphtheria toxin catalyzes the elongation factor-2 (EF-2) ribosylation of ADP
and inactivates it [Figure 3].
The tox gene is encoded by a phage
and is controlled by the DtxR (diphtheria toxin repressor gene )suppressor
protein, which forms an iron complex, DtxR-Fe that binds DNA and restrains the
expression of tox [Figure 4].Therefore, diphtheria toxin is only synthesized
under low iron conditions, indicating that iron release from target cells can
be stimulated [10,11].
Diphtheria Vaccination: Four forms
of vaccines used today to protect against diphtheria and other diseases as
well: Vaccines for diphtheria and tetanus (DT), diphtheria, tetanus, and
acellular pertussis (DTaP), tetanus and diphtheria (Td), tetanus, diphtheria,
and acellular pertussis (Tdap). Babies and kids under the age of 7 receive DTaP
or DT while older kids and adults receive Tdap and Td.
Passive and active immunization:
Passive immunization of equine origin through diphtheria antitoxin (DAT) is
highly effective in the treatment of diphtheria though it is not a substitute
for active immunization using diphtheria toxoid. Nonetheless, antitoxin is an
effective diphtheria medication, and can reduce morbidity as well as mortality.
Should be administered diphtheria antitoxin (DAT) as soon as possible after the
initiation of the disease, once the toxin has reached the host cells the
antitoxin is unaffected. You will administer the entire therapeutic dose at one
time. The recommended amount of antitoxin ranges from 20,000 to120,000 units
with larger amounts recommended for individuals with severe local lesions and
longer periods since the onset. New approaches include developing monoclonal
antibodies to diphtheria toxin or developing recombinant modified toxin
receptor molecules to bind toxin to diphtheria. To date, however, no monoclonal
diphtheria toxin antibody has been approved for clinical use, so treatment is
still based on DAT. The toxoid to diphtheria is used for successful
immunization. Diphtheria vaccines are based on the toxoid diphtheria, a
modified bacterial toxin that causes defensive antitoxin. immunization with DT
by combination the diphtheria toxoid with tetanus toxoid as DT (for use < 7
years of age) or Td (for use < 7 years of age) or as DT(a)(w) P or TdaP with
tetanus and pertussis vaccine (acellular= a, wholecell= w). Diphtheria toxoid
associated with other vaccine antigens such as polio (IPV), hepatitis B, and
type b Haemophilus influenzae.
The efficacy of diphtheria
antitoxin antisera
The antigen binding with the corresponding
Abs determines the basis for evaluating vaccines, therapeutic antisera, and
human and population immune functions. Composition of the antigen produced,
aside from assay types, Abs complex interaction is mainly determined by
reactant heterogeneity, interaction specificity, and reactant concentration.
These interactions were widely used in many assays, in which one of the
reactants was calculated by the arbitrary set-end stage. A variety of methods
are commonly used to titrate diphtheria antitoxins, including both in vivo and
in vitro assays. While in vivo study has the advantage of testing the Abs,
which essentially neutralizes the toxin, it is relatively costly and
repeatable. Several complementary quantitation assays have been developed for
DT and antitoxins [12,13]. The total Abs content and the Abs avidity have not
been precisely calculated for any of those measures. Although the measured
traits could be very distinct in different assays, the determined titers were
found to be satisfactory in various applications. The heterogeneity of
contributing factors was essentially largely overlooked. Abs ‘avidity was
recognized as an effective vector in restraining the defense against various
diseases [14].
Avidity as a criterion for the
efficacy of the vaccine against diphtheria: The term avidity refers to how
closely it binds an antibody to their antigen. Affinity refers to the strength
of the bond between an antibody and its antigen. However, several isotypes of
antibodies are multivalent, and bind to several antigens. The strength of this
overall partnership is the covetousness of avidity. Antibodies (Abs) avidity to
diphtheria toxin (DT), toxoids (DTo) and the diphtheria toxin binding site
(DTBS) were investigated in sera from guinea broad vaccinated with specific DTo
during 2004. Measuring avidity by the thiocyanate method showed that when
maturing, Abs maturation trends to the corresponding DTo were not quite
different. In the DTBS affinity variations of up to 20 folds were observed as
calculated by the tissue culture technique and expressed as equilibrium
constant (K). Abs ‘avidity to either the corresponding DTo or the DT could not
be correlated with the vaccine’s effectiveness, while the vaccine’s efficacy
could be measured by its association with the DTBS. This can be represented in
any procedure in terms of measuring precision. The thiocyanate procedure
measures the average avidity to complex antigens with multiple epitopes while
the tissue culture procedure allows the DTBS affinity of Abs to be determined.
It is concluded that the priority in testing new vaccines should involve
measuring the avidity of Abs to the known protective epitome [15].
Defense against different
pathogens depends mainly on antibodies, where each antibody is specific to a certain
antigen to reach maximum effect and this is the major part of humoral immunity.
A research to determine the relevance and reliability of the non-functional
Enzyme-Linked Immunosorbent Assay (ELISA) for potency testing of diphtheria
toxoid-containing combination vaccines was initiated in January 2000 [16].
According to conventional antibody standard, a strong enzyme-linked
immunosorbent assay (ELISA) was proven to identify the quantity of
anti-diphtheria antibodies in human serum, researches showed very accurate
results where recovery have reached up to 97.06 %. The ELISA test mentioned for
the quantitation of diphtheria antitoxin is a valuable tool for evaluating
immunological defense against diphtheria and could be particularly useful for
population studies, since it is economical and practical for large-scale
routine purposes.
A quick hexavalent bead-based
method was developed by [17] to improve preclinical assessment of serological
immune responses to the individual components of DTP combination vaccines
diphtheria, tetanus, and pertussis (DTP). The sensitivities of the mouse DTP
avidity multiplex immunoassay (MIA) per antigen were comparable to those of the
six individual in-house avidity ELISAs, and strong correlations of the IgG
concentrations obtained for all antigens tested by both methods were shown. The
normal and active mouse DTP MIAs were reproducible for all antigens, with
strong variability (CV) intra- and inter-assay coefficients. Ultimately, a
retrospective study of the production and avidity maturation of differentIgG
antibodies in mice demonstrated the utility of the assay. They conclude that
the hexaplex mouse DTP MIA is a reliable, responsive and high-throughput
alternative for ELISA in preclinical vaccine studies to investigate the quantity
and quality of serological responses to DTP antigens [18]. Estimate avidity by
a Modified ELISAs by using chaotropic agents and calculating the degree to
which they interfere with the interaction between the antigen and the antibody.
The idea behind the test is the greater an interaction’s avidity the less
sensitive it is to the effects of the chaotropic agent. The test was highly
reproducible and identified a wide variety of avidities for antibodies.
Consequently, a GuHCl-modified ELISA is an appropriate approach which can be
used within a clinical trial setting to evaluate HPV-specific antibody avidity
indices.
Conclusion
Diphtheria is mainly regulated by
vaccination, and by high immunization coverage ensures adequate herd immunity.
The initiation of diphtheria outbreaks represents insufficient coverage of the
vaccine. This epidemic was likely the result of the reintroduction by
contaminated migrants passing through mining districts and poor vaccination
levels of previously eradicated diseases [19]. In addition to several
outbreaks, thousands of cases of diphtheria are still recorded annually from
many countries in Asia and Africa. Changes in diphtheria epidemiology have been
identified across the globe. Toxigenic Corynebacterium is prevalent. Highlights
the need for effective clinical and epidemiological investigations with a view
to rapid diagnosis and care of sick persons and public health. Additional
studies for new assays and limits are needed to increase the current level of
vaccine potency. These attempts to improve assays are expected to stimulate the
production of the diphtheria vaccine and lead to self- of the vaccine.
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