A review of COVID-19 vaccines and major considerations for diabetic patients

Saber Soltani1,2, Milad Zandi1,2, Parisa Shiri Aghbash3, Masoud Rezaei4, Nader
Mohammadzadeh5, Alireza Afsharifar6, Vahdat Poortahmasebi3, *

1- Department of Virology, School of Public Health, Tehran University of Medical

Sciences, Tehran, Iran.
2- Research Center for Clinical Virology, Tehran University of Medical Sciences,
Tehran, Iran.
3- Department of Bacteriology and Virology, Tabriz University of Medical Sciences,
Tabriz, Iran.
4- Plant Virology Research, University of Shiraz, Shiraz, Iran.
5- Health Reference Laboratory, Tabriz University of Medical Sciences, Tabriz, Iran.
6- Department of Plant Protection, University of Shiraz, Shiraz, Iran.

Corresponding Author:

Vahdat Poortahmasebi, PhD in Medical Virology, Department of Bacteriology and Virology,

Tabriz University of Medical Sciences, Tabriz, Iran.

Tel/Fax: +98-4133364661

PO-Box: 5166614766

Email: poortahmasebiv@tbzmed.ac.ir

Abstract:

The necessity and impact of SARS-CoV2 on the world's health have led to developing and
producing practical and useful vaccines for this deadly respiratory virus. Since April 2020, a
vaccine for the virus has been developed. Given that comorbidities such as diabetes,
hypertension, cardiovascular disease are more prone to viruses and the risk of infection,

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/bab.2076.

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vaccines should be designed to protect against high-risk respiratory illnesses. Including
SARS, MERS, influenza, and the SARS-CoV-2 provide a safe immune response. Here, we
review the information and studies that have been done to help develop strategies and
perspectives for producing a safe and ideal vaccine to prevent COVID-19 in normal people,
especially at high-risk groups such as diabetes patients.

Keywords: COVID-19, SARS-CoV-2, Vaccine, Diabetes

Graphical Abstract:

Highlights:

 The COVID-19 caused by SARS-CoV-2.

 High-risk groups for COVID-19, such as diabetic patients, have immunodeficiency.
 Vaccine design against SARS-CoV-2 is vital to decreasing morbidity and mortality of
COVID-19 in diabetic patients.

1. Introduction:

In early 2020, the coronavirus disease 2019 (COVID-19)outbreak was caused by the severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1), that they are a group of viruses
that are classified in the Coronaviridea family (2). These viruses have features such as a
nucleocapsid of helical symmetry, RNA-positive single-stranded genomes with a length of 27
to 34 KB (3), and an envelope on their surface (4).

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Coronaviruses in mammals and birds cause respiratory tract disease and diarrhea and are
potentially fatal in humans(4). In this case, the severe acute respiratory syndrome coronavirus
(SARS-CoV) and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) can be
mentioned. The recent SARS-CoV-2 and the SARS-CoV and MERS-CoV are related to the
genus Beta-coronaviruses (1, 5). In 2002-2003, the world experienced the first deadly
coronavirus infections, known as SARS-CoV, characterized by high fever and ultimately
leads to shortness of breath and pneumonia (4). The syndrome first spread to southern China
and led to 774 deaths in 26 countries (4). Despite significant efforts to develop the vaccine,
no vaccine was available, and the disease was discontinued in 2004 (4). Also, in September
2012, the world's second coronavirus outbreak MERS-CoV occurred.
The infection spread from Saudi Arabia and was characterized by mild respiratory symptoms,
but the disease may lead to acute respiratory syndrome and, eventually, death (4). The
syndrome also killed 858 people in 27 countries (6). There are still reports of MERS-CoV
cases, but they have not been widespread since 2015 (7). Furthermore, like SARS-CoV, there
is no vaccine available for MERS-CoV (4). The COVID-19 is currently a pandemic disease
caused by SARS-CoV-2, first reported in December 2019 from Wuhan, China (4, 8).
Symptoms include fever, cough, and shortness of breath. Moreover, this disease can
ultimately lead to pneumonia and several organs' failure, especially in the elderly and those
with other underlying diseases (4, 8).
A retrospective cohort study reported that absolute and relative mortality has declined overall
in people with diabetes in Hong Kong (9). Despite the potential for COVID-19 outbreaks,
such as influenzas like deaths, diabetes is a major risk factor for adverse outcomes (10, 11).
Mortality among older people with diabetes has been reported to be due to pneumonia. It is
currently the highest mortality rate in this age group in patients with cardiovascular disease
and cancer (9). Similar evidence from the risk of infection among diabetics people, for
SARS-CoV and the MERS-CoV, are reported to be infected, mostly in Saudi Arabia (12-14).
Also, a combined analysis of 46,248 cases showed that, high blood pressure (17%, 95%
confidence interval [CI] 14–22%), diabetes mellitus (8%, 95% CI 6–11%), cardiovascular
disease (5%, 95% CI 4–7%) and respiratory complications (2%, 95% CI 1–3%) are the most
common (15). It has been reported that the severity of COVID-19 may be significantly
increased through environmental factors such as air pollution and smoking and underlying
diseases such as high blood pressure, diabetes, and underlying heart and respiratory disease
(16). A variety of factors, including host genetic susceptibility to infection, immune and
cellular immune defense mechanisms, as well as factors such as low blood pressure and nerve

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damage, and ultimately metabolic changes, can expose diabetic patients to further infection
(17). It has also been shown that pancreatic tissue is a potential target tissue for viral
infection, leading to impaired glucose metabolism, resulting in COVID-19 disease leading to
hyperglycemia (18-20). As mentioned above, diabetes and hyperglycemia as one of the most
common complications can lead to secondary infections and increased death (21-24). An
important aspect of the SARS-CoV-2 vaccine develpment is caring for people with diabetes
(11).

2. Diabetes and its immunodeficiency:

As mentioned, the risk of infection increases in patients with diabetes, but the evidence for
their acquired immunity is still incomplete (25). It has also been shown that the rate of
infection is more severe in patients with diabetes (26). These infections include bacterial and
fungal infections (17, 27, 28), (The most critical clinical infections include skin infections,
urinary tract infections, and respiratory tract infections) (29, 30); however, patients are more
sensitive to these infections due to metabolic disorders (26). It has also been reported that
deficiency in leukocyte function can increase soft tissue infections, lower respiratory tract
infections, and urinary tract infections in people with diabetes (26). Other cells involved in
immune responses, including B lymphocytes, which are involved in responding to infections,
have also been reported to be involved in specific immune processes, such as humoral and
cellular responses (26). Other factors, such as circulatory abnormalities in patients with
diabetes, may play a critical role in causing these infections or interfere with their response to
treatment (31). As we know, host defense against these infections depends on innate
immunity (e.g., phagocytic function) and adaptive immunity (antibody activity against T-cell-
dependent antigens and T-independent cells). B cells' unique production of antibodies
requires antigen-dependent T cells and their colonial expansion (32). The precursor of these
active T cells is due to the supply of antigen, antigen absorption, and processing in T cells
due to the function of antigen-presenting cells (APC) (25). In type 1 diabetic patients, T cell
proliferation is significantly reduced compared to type 2 diabetic patients and normal
individuals (25). This reduction indicates a disordering effect on T cells' activity in type 1
diabetic patients. These cells have also been reported to require antigenic and stimulatory
signals than memory T cells (33).
T cell disorder or APC dysfunction may be possible causes of T cell activation disorder (25).
Researchers have also shown that "reduced peptide-binding" by certain-chain alleles of the

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human leukocyte antigen-DQ (HLA-DQ) molecule is directly related to the susceptibility to
type 1 diabetes (34, 35). Besides, it has been shown that deficiency in the expression of the
specific protein tyrosine kinase (p56lck) in some type 1 patients is strongly associated with
HLA haplotype (25, 36). Defense against an infectious agent usually depends on developing
a unique immune response of T cells or B cells. T cells' weak response in patients with type 1
diabetes may lead to a promotion in intestinal bacterial proliferation and the early stages of
infection, resulting in increased susceptibility to infectious diseases, a prolonged increase in
disease, or an increased risk of complications (25, 37). Recently studies have shown that
angiotensin-converting enzyme 2 (ACE2) may have a role in diabetic ketoacidosis. ACE2, as
a cellular receptor, has an essential role in SARS-CoV-2 infection. Its expression is decreased
after endocytosis of SARS-CoV-2. ACE2 acts as a catalyst agent to convert angiotensin II to
angiotensin 1-7. Coronavirus infection causes down-regulation of ACE2 expression which
can affect pancreatic beta cell function (38) (Figure.1).
As a result, immunodeficiency in response to primary immune-response in type 1 diabetes
may be critical for new vaccination (25).

3. The types of vaccines available for CoV:

Studies have shown that SARS-CoV-2 is quite similar to SARS-CoV in terms of genome
sequence analysis, resulting from previous research that has shown promising results in the
field of protective safety responses against SARS-CoV. It can lead to prospects for vaccine
development for SARS-CoV-2 (1, 5, 39). In addition, it has been shown that antibodies
response to SARS-CoV N protein, which is an immunogenic protein and produced
significantly during infection, are prevalent in patients with SARS-CoV (40-42). It has also
been shown that in these patients, T cells produce long-term responses (43-45). Due to the
significant genetic diversity, it is debatable whether epitopes that provide an immune
response against SARS-CoV are effective against SARS-CoV-2 despite the apparent
similarities between the two viruses (1). It has also been reported that only 23% and 16% of T
cells and B cell cells in SARS-CoV overlap with SARS-CoV-2, and these epitopes, among
SARS- CoV-2 sequences, also have no visible mutations (as of February 21, 2020) (1). As a
result, it indicates their ability to produce strong T cells or the appropriate antibody responses
in SARS-CoV-2. It has also been reported that a significant amount of SARS-CoV-derived
epitopes, which is equally present in SARS-CoV-2, has been implicated in research on
vaccine production to induce T cells' immune response, which is long-acting immunity.

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Provide duration in SARS-CoV is particularly encouraging (43, 45, 46). It has been shown
that antibodies derived from SARS-CoV may target the receptor-binding motif in the S1
subunit of the S protein in SARS-CoV-2, which is not practical due to the extensive genetic
mismatch in this domain (1, 47, 48). As a result, vaccines that try to induce antibodies
targeting S2 linear epitopes may be useful and should be considered in the future (1).
The vaccine is designed to boost our normal immune response to an invasive virus by
stimulating it to detect specific antigens and molecules on pathogens' surface (49). Typically,
the immune system responds to these antigens by producing special immune cells that
directly attack the pathogen or produce proteins called antibodies (49). An unregulated
immune response may also involve antibodies or immune cells, or both. As a result of the
reverse immune response, or in other words, overexpression of the immune system, it can
occur in a variety of ways. One of them is an antibody-dependent enhancement (ADE), a
process in which the virus increases the infection by infiltrates the antibodies, or cell-based
amplification. This process involves allergic inflammation caused by Th2 immunopathology
(49).
Although no vaccine is available for SARS-CoV and MERS-CoV, past and current efforts to
vaccinate against these diseases could be a great value in producing an effective vaccine for
COVID-19 (4).

3.1. Vaccine for SARS-CoV:

In 2002-2003, after the SARS--CoV epidemic, many efforts were made to develop a vaccine
to prevent the disease (4). Most subunit vaccines target the Spike (S) of the virus that uses it
to bind and enter host cells (4, 50). As a result, a vaccine that provides robust immune
response to the protein will prevent the virus from entering the host cells (4). Many studies
have been performed on vaccines based on live-attenuated or inactive viruses, recombinant
viral vectors, DNA vaccines, virus-like particles (VLPs), and soluble proteins (4). Finally,
live-attenuated and inactivated viruses were identified as vaccines based on the whole SARS-
CoV (4). The virus is ineffective, and its virulence has been significantly reduced by
eliminating the virus genome's components or using physical or chemical methods (51). In
the case of recombinant viral vectors, different strains of SARS-CoV viruses that are capable

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of infecting the host cell are altered by genetic engineering to express the components of
SARS-CoV (52). VLPs are also multi-protein and non-infectious structures composed of viral
proteins and are located in virus-like structures (53). It has been reported that vaccines have
reached the clinical stage (phase I), based on inactive SARS-CoV, DNA, and soluble proteins
based on SARS-CoV S glycoprotein (4, 54, 55). According to SARS-CoV virulence, no
studies have been performed in humans, and therefore the protective effect of vaccines has
not been evaluated (4).

3.2. Vaccine for the MERS-CoV:

In 2012, during the outbreak of MERS-CoV, various vaccines, including subunit vaccines
based on glycoprotein S, vaccines based on inactive and attenuated viruses, recombinant viral
vectors, nanoparticles, DNA vaccines, and soluble proteins had been developed mainly in
animal models (4, 56). It has also been suggested that only DNA-based vaccines are currently
being tested in clinical trials (Phase I) (57), along with other vaccines, including modified
vaccinia virus Ankara (MVA) and adenoviruses that are currently in the clinical stage (4).

3.3. Correlates of immunity:

It has been shown that neutralizing antibodies (58) against S glycoprotein in SARS-CoV and
MERS-CoV plays a vital role in creating immunity against these coronaviruses (59, 60).
Recent studies have shown that passive immunization methods focusing on MERS-CoV and
SARS-CoV S glycoproteins produce high levels of neutralizing antibodies in animals (61-
67). In experiments with MERS-CoV, it has been reported that vaccination with DNA-based
vaccines in non-human primates leads to the induction of CD8 + T cell responses, in addition
to neutralizing antibodies (68). Also, vaccines based on protein and vaccines based on DNA
and protein combination lead to long-term immunity in mice and maca(68, 69). In general,
these studies have focused more on the induction of stable neutral antibodies during
vaccination than on the induction of T cells (4). However, it has been reported that the
response of T cells may also lead to the elimination of viral infection during infection,
eventually leading to the patient's recovery (70, 71). As a result, the induction of both
humoral and cellular immune responses leads to the effective elimination of the virus and
recovery from the disease. The vaccine is ideal for long-term immunity (4). In SARS-CoV

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cases, memory T cells can be detected up to 6 years after infection and neutralizing
antibodies up to 24 months after infection, leading to a certain level of immunity due to these
humoral and cellular responses (43, 72). In MERS-CoV cases, there is little information
about memory B cell production, but it has been reported that neutralizing antibodies for 34
months and T memory cells, T CD4 and CD8 + cells were detected 24 months after infection
(71, 73). Other human coronaviruses have been reported to provide evidence of long-term
immune induction (4). Studies on the safety of SARS-CoV and MERS-CoV vaccines have
been reported to be almost inaccessible. There are also concerns about the induction of ADE
as well as other side effects of vaccination or re-exposure to the virus. In fact, ADE is a
prosses that neutralizing antibodies against virus proteins, which strengthen the virus's entry
into host cells, eventually lead to an increase in virus infection (4). In addition, the use of a
receptor binding domain (RBD) or subunit of S1 glycoprotein S can lead to the prevention of
ADE as well as the induction of neutralizing antibodies (4). As a result, the induction of
antibodies associated with the glycoprotein S region, in order to effectively neutralize the
virus, leads to the inhibition of the induction of non-neutralizing antibodies associated with
other areas of glycoprotein S (4). Despite recent evidence, vaccines based on these areas of S-
glycoproteins, which have recently been studied, also appear to be induce high titers of
neutralizing antibodies and a certain level of immunity in small animals and non-human
primates (66, 68, 74, 75).
However, no evidence of ADE has been reported in human patients (49). The utilize of
adjuvants leads to the prevention of adverse side effects of coronavirus vaccination (76).

4. Recommended vaccines for COVID-19:

Currently, researchers are working hard to find an effective vaccine to treat the COVID-19,

but there are many scientific and logistical challenges involved. One of the most important of

these challenges is finding out how the immune system works with both the pathogen and the

vaccine itself and the vital strategies for trying to produce a safe and effective vaccine (49).

According to the World Health Organization (WHO), there are 5 and 71 candidate vaccines

for COVID-19 in clinical and preclinical evaluation, respectively (as of April 20, 2020).

(Table 1) (77). There are five platform cases of vaccines against SARS-CoV-2, which are in

the clinical evaluation, including non-replicating viral vector, inactivated, DNA, and RNA.

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Approximately all vaccines in the preclinical evaluation are in phase 1 clinical evaluation

except one of the non-replicating viral vector vaccines in phase 2. Also, there are various

platforms for vaccines in “preclinical evaluation,” including DNA, RNA, inactivated, non-

replicating viral vector, live attenuated virus, protein subunit, replicating viral vector, VLP

(77, 78).

Scientists also need to know whether the vaccine, like previous vaccines, stimulates and

strengthens the immune system. Contrary to current evidence, some animals or humans who

are vaccinated after virus exposure showed a more severe response in comparing those who

have not been vaccinated (79). Despite all the efforts mentioned, including the recommended

vaccines for COVID-19, the following can be mentioned:

4.1. Whole Virus Vaccines

One of the strategies for viral vaccinations is that the Live-attenuated or inactive whole virus
vaccines. According to an industrial newsletter, Johnson & Johnson, one of the multinational
companies, examines the COVID-19 vaccine (80). Like the Ebola vaccine platform, they
make the Janssen Ad-Vac® adenovirus vector and produce it in their PER.C6® line
technology (80). In addition, a live influenza vaccine has been shown at the University of
Hong Kong to produce SARS-CoV-2 proteins, and eventually developed Codagenix, which
attenuate the virus through “Codon deoptimization” also examines SARS-CoV-2 vaccine
strategies (80). Among the advantages of the whole virus, vaccines are intrinsic immunity
and stimulate toll-like receptors (TLR), including TLR 3, TLR 7/8, and TLR 9. It has been
shown that live virus vaccines require extensive testing to confirm safety due to increased
infection following vaccination with live or killed whole SARS-CoV vaccines (81).
Furthermore, Dipperslow et al. have been shown that patients with diabetes have insufficient
immune responses after vaccination with an inactivated influenza virus vaccine (82). Also,
Zoe et al. Showed that the antibody response in diabetic mice decreased and only
immunization with higher doses of inactive influenza vaccine protected the virus in diabetic
mice (83).

4.2. Subunit Vaccines

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As mentioned earlier, subunit vaccines for both SARS-CoV lead to an immune response to
the virus glycoprotein, thus preventing it from binding to the host ACE2 receptor (81). It has
also been reported that Novavax has produced virus-like nanoparticles based on recombinant
glycoprotein S. In contrast, Clover Biopharmaceuticals has developed a subunit vaccine
modified from a trimerized SARS-CoV-2 S glycoprotein using Trimer-Tag technology (80,
84, 85). However, some full-length S glycoproteins in SARS-CoV also promote infection and
eosinophil infiltration (80). It has also been reported that, when alum adjuvants are used, the
SARS-CoV vaccine based on RBD produces a high level of immunity to the homologous
virus challenge. (81). It has been reported that, because SARS-CoV and SARS-CoV-2 RBDs
have more than 80% similarity in amino acid sequence and bind to the common ACE2
receptor, it has led to the development of subunit vaccines using Glycoprotein S (80).

It has also been shown that successful Hepatitis B Virus (HBV) vaccination (HBsAb-
positive, HBcAb-negative, and HBsAg-negative with HBV vaccination) is associated with a
33% reduction in the risk of developing diabetes (86). Researchers identified the high
possibility of the RBD-based mRNA vaccine for the reduction of the COVID-19 pandemic
severity. (87) In comparison to the RBD of SARS-CoV-2 and SARS-CoV, The SARS-CoV-2
RBD exposes a significantly higher binding affinity to the ACE2 receptor, and block this
binding with RBD-induced antisera could inhibiting the infection from hosting cells as a
potential vaccine for prevention of SARS-CoV-2 and SARS-CoV infection. (88)

4.3. Nucleic Acid Vaccines

According to studies, there are several major biotechnologies for the development of the
COVID-19 nucleic acid vaccine. For instance, Inovio Pharmaceuticals is developing a DNA
vaccine, while some are examining RNA vaccines, such as Moderna Therapeutics and Cure-
vac(80). It was shown that, in 1993, DNA vaccines were first developed in mice to provide
an adequate immune response to influenza, which, unfortunately, has not been studied in
humans for decades. Recently, new changes have improved the function of nucleic acid in

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humans, and as a result, may lead to the first usable human nucleic acid vaccine(80). It is also
reported that a healthcare biotechnology company, Entos Pharmaceuticals, uses a nano-
medical platform called Fusogenix to examine the DNA vaccine to prevent COVID-19 (89).
Fusogenix is a proteo-lipid vehicle (PLV). In recent studies, medicines enable the formulation
of suitable DNA vaccines to act as an influenza vaccine, converting the vaccine into a
plasmid DNA that encodes several antigens of essential SARS-CoV-2 proteins and ultimately
leads to an adequate immune response (89). At least half of the vaccines currently include
live viruses, recombinant protein subunits, and nucleic acids, which are types of vaccines to
prevent COVID-19 (89).

Studies have shown that DNA vaccination with the influenza virus is studied in animal
models and induces cellular immune responses (90, 91). Diabetes also reduces the capacity of
the DNA NP (nucleoprotein) vaccine to induce cytotoxicity response, lymphocyte
proliferation, and IFN-ᵧ production. Besides, it has been reported that DNA vaccines must
induce T CD4, T CD8, and B cells to be effective (92, 93).

4.4. Virus-Like Particle

In Canada’s Medicago studies, they produced a VLP from SARS-CoV-2 just 20 days after
obtaining the SARS-CoV-2 genome (89). Indeed, VLPs are multi-protein structures that
resemble natural viruses while lacking the virus genome and can therefore be used to
stimulate the humoral and cellular immune systems, leading to a response to the virus without
the risk of infection (94).

4.5. ChAdOx1 nCoV-19

Recently, it has been reported that the ChAdOx1 nCoV-19 vaccine, developed in
collaboration with the University of Oxford's Jenner Institute and the Italian pharmaceutical
manufacturer of company Advent Srl, is being investigated. The ChAdOx1 virus vector,
developed at Oxford University, was developed against MERS-CoV (95). The vaccine
contains an attenuated adenovirus that can produce glycoproteins (S) of SARS-CoV-2,
eventually leading to the production of endogenous antibodies to these proteins and,
ultimately, to SARS-CoV-2 (89).

4.6. Vaccine (Avoid side effects)

Given that we expect vaccine production strategies to be implemented quickly. We believe
that after the vaccine is proven to be effective (possibly theoretically), it will be distributed to

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millions or billions of people (96). Recent studies have found that the side effects of the
vaccine cannot be evaluated. For instance, because the amino acid sequence of the virus, like
other viruses, may cross-react with the human amino acid sequence, one of the side effects of
the vaccine can be autoimmune diseases, especially in people with Genetically predisposed to
autoimmune disease (96-99). Recently been reported that by examining the virus amino acids'
pentapeptides and selecting immunogenic cases, the possible side effects of autoimmune
diseases can be reduced (96). These peptides can also generate an affinity column to extract
unique antibodies to the virus in the serum of patients recovering from COVID-19. It has also
been shown that Intravenous Immunoglobulin (IVIG) can be useful in an infectious condition
without any side effects from the transmission of the innate natural immune system of healthy
people to the infected person (100-102).

4.7. Vaccine and immune response

Recently, it has been hypothesized that, based on vaccine formulations (tetanus, diphtheria,
Bordetella pertussis) that lead to the recurrence of CD4 + T memory cells after the first
contact with COVID-19, which can be effective before severe respiratory illness and acute
respiratory distress syndrome (ARDS) )301(. The CD4+ T cells can boost the
immunopotentiation against known coronaviruses, and antibodies can prevent disease
progression. In addition, after stimulation by vaccine formulation, the specific immune
response against COVID-19 can be formed faster and longer, thus preventing severe lung
damage and disease progression (103). It has been reported that this method can be useful not
only during infection but also before it. Indeed, people can have a more robust immune
system when exposed to COVID-19. Also, the immune response is not limited to one antigen
but will be effective against broader antigens from the virus (103).

5. Diabetic patients immune response to the variety of vaccines available, such as

influenza:

As mentioned in the previous section, poor control of diabetes, high blood sugar, and insulin
can interfere with an individual’s immune response, leading to a promotion prone to the
infection (104). Diabetes disrupts several aspects of the host's immune response. The
infection rate is directly related to blood glucose levels and is more severe and prolonged
than normal individuals (17).

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Adjuvant therapies, including Biological Response Modifiers (BRMS), should be considered
in diabetic patients (17).
It has been reported that in people with type 1 diabetes (insulin-dependent), the total amount
of T lymphocytes and the number of T lymphocytes (helper) decreases and leads to a
decrease in the CD4 / CD8 ratio. This deficiency may be caused by both factors, such as
decreased insulin levels or decreased insulin activity (105). The antibody response has been
similar in people with diabetes and normal individuals to the influenza vaccine(106). For
example, in the case of influenza, some components of the vaccine may have already been
processed by the host immune system, which may be equivalent to a secondary immune
response. However, more research is needed (17). Therefore, a decrease in primary and
cellular immune response (as in the case of hepatitis B) can be due to a defect in antigen
detection. This defect may be genetically related to a defect in macrophage function in
antigen recognition (17). The secondary immune response (such as activation of memory T
cells after influenza vaccination) may also depend on the patient's metabolic status. Because
diabetes can lead to infection, controlling the metabolic status to prevent infection is of
paramount importance (17).
Annual vaccination against influenza is also recommended for people with diabetes in Europe
and UK, especially for patients with long-term diabetes who are at risk for upper respiratory
tract infections and pulmonary disease (17, 107) because of the humoral rate of cellular
responses diabetic patients decreases. Poor glucose control is also linked to the level of
immune defense in patients (17).
Studies have shown that during the influenza vaccination, the immune response is similar in
people with diabetes and normal people (82, 106, 108). Therefore the influenza vaccine may
be useful in this high-risk group (107). A study has also reported that the DNA pNP vaccine
cannot induce immunity through appropriate cellular function in diabetic mice. These results
provide a new perspective on DNA immunization for infectious diseases in diabetes (109).

6. Conclusion:
Trying to spread the vaccines used for respiratory diseases such as SARS-CoV, MERS-CoV,
influenza will lead to sight on how to get the appropriate vaccine to prevent COVID-19.
Because the severity of the infection is higher in diabetic patients and other people prone to
infection, and because they are more at risk for disease and death, it is important to try to
produce a vaccine that adequately induces an immune response in these people. As
mentioned, glycoprotein S in coronaviruses can provide adequate immunity. As a result of

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cross-protection between viruses in this family, vaccine design that contains this protein is
likely to be effective. According to previous sections, subunits of vaccines, such as the HBV
vaccine and attenuated vaccines such as the influenza vaccine, are useful in diabetics and
have shown a similar immune response to normal individuals. It may be a strategy for the
production of the appropriate vaccine in diabetics to prevent COVID-19. However, each of
the proposed vaccines in this review article, in order to achieve the commercially available
and testing stages and to be able to initiate clinical progress, is the first stage of clinical trials,
including phase 1 clinical trials for safety and immunogenicity, and later, phase 2 and phase 3
trials for both safety and efficacy. Finally, the vaccine design against SARS-CoV-2 is vital to
decreasing morbidity and mortality of COVID-19 patients. Currently, several SARS-CoV-2
vaccines are in the different clinical trials stages. Several vaccine approaches have different
advantages and limitations. An ideal vaccine will require to be safe, efficient, long-lasting,
and available to considerable populations.

Abbreviations:
coronavirus disease 2019 (COVID-19)
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
severe acute respiratory syndrome coronavirus (SARS-CoV)
Middle East Respiratory Syndrome coronavirus (MERS-CoV)
antigen-presenting cells (APC)
human leukocyte antigen (HLA)
angiotensin-converting enzyme 2 (ACE2)
antibody-dependent enhancement (ADE)
NP (nucleoprotein)
Spike (S)
virus-like particles (VLPs)
modified vaccinia virus Ankara (MVA)
receptor-binding domain (RBD)
World Health Organization (WHO)
proteo-lipid vehicle (PLV)
Intravenous Immunoglobulin (IVIG)
Acute respiratory distress syndrome (ARDS)
Biological Response Modifiers (BRMS)

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Figure Legends

Figure.1: SARS-CoV-2 & Diabetic Ketoacidosis

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Table 1. Candidate Vaccines of SARS-CoV-2 in Clinical Evaluation

Type of candidate vaccine Platform The current stage

of clinical
evaluation

ChAdOx1-S1 Phases 1/2, 2b, 3

Non-Replicating
Viral Vector

Adenovirus Type 5 Vector Phases 1, 2

Adeno based Phase 1

Inactivated+ alum Phase 3

Phases 1, 2
Inactivated
Inactivated

Inactivated
Phases 1, 2

Inactivated
Phase 1

DNA plasmid vaccine with Phases 1, 2

electroporation

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 DNA

Phases 1, 2
DNA plasmid vaccine

DNA Vaccine
Phase 1
(GX-19)

LNP2
encapsulated
mRNA Phases 1, 2

RNA

3 LNP-mRNAs Phases 1, 2

Full-length recombinant SARS CoV-2

glycoprotein nanoparticle vaccine Phases 1, 2
adjuvanted with Matrix M Protein Subunit

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