Introduction

Immune System
The immune system protects the body from potentially harmful substances by
recognizing and responding to antigens. Antigens are substances (usually
proteins) that are found on the surface of cells, viruses, fungi, or bacteria. Inert
substances, such as toxins, chemicals, drugs, and exogenous particles, it can
also be antigens, which are substances capable of stimulating an immune
response in the human body. The immune system recognizes and destroys
substances that contain antigens (Vega-Robledo G. 2008).
The human immune system is divided into two stages or two classes, the
innate immune system and the adaptive immune system.
Innate Immune System
Innate, or nonspecific, immunity is a defense system that any person born
with, it protects you against all antigens. Innate immunity consists of barriers
that prevent harmful materials from entering the body. These barriers form the
first line of defense in the immune response. Examples of innate immunity
include:
 Macrophages and Dendritic Cells, works as sentinels
 Cough reflex
 Enzymes in tears and skin oils
 Mucus, which traps bacteria and small particles
 The Skin
 Gastric Acid
Innate immunity deals with shared structures against different microbes and
substances. Innate immunity also comes in the form of a protein chemical,
called innate humoral immunity (Brandan N. Aquino-Esperanza J., 2007).
Among the effector mechanisms of innate immunity are:
 Epithelial barriers: they act by separating the outer from the inner
environment of the host, such as the skin, the respiratory epithelium and
the digestive epithelium. Several proteins and molecules act here to help
in its defense, such as interleukins, defensins, and cryptocidins. The
 contribution of immune cells silk thanks to intraepithelial T
lymphocytes, B lymphocytes, neutrophils, monocytes and macrophages,
NK cells.
 Effector proteins: the complement system where, through the classical
pathway and the alternate pathway, the system is capable of recognizing
microorganisms foreign to the host in order to activate the adaptive
immune system. The participation of the C-reactive protein, called acute
phase, is key in the activation of the complement system. (Brandan N.
Aquino-Esperanza J., 2007).
Adaptative Immune System
It is a much more evolved defense mechanism, which is stimulated after
exposure to infectious agents, and whose defensive capacity and intensity
increases after each subsequent exposure to a certain microorganism. There
are two types of adaptive immunity, cellular and humoral immunity. Both
work together to remove microorganisms. (Brandan N. Aquino-Esperanza
J., 2007).
 Cellular immunity: it receives this name because its mediators are
cells, unlike humoral immunity whose mediators are molecules. T
cells, or T lymphocytes, are the main effectors of cellular immunity.
These cells basically in charge of eradicating intracellular
microorganisms. There a two subpopulations of T lymphocytes,
helper T (CD4 +) and cytolytic or cytotoxic T (CD8 +). T cells, in
turn, are subdivided into Th1 and Th2. This cell type recognizes the
antigenic peptides of intracellular microorganisms, when they are
expressed on the surface of the host cell associated with MHC I or
MHC II molecules, depending on who is the effector T Lymphocyte,
CD4 + or CD8 + respectively. (Brandan N. Aquino-Esperanza J.,
2007).
 Humoral immunity: its mediators are antibodies and complement
proteins. Antibodies useful for host defense are found in the blood,
but are produced by B lymphocytes or plasma cells in the lymph
nodes. Brandan N. Aquino-Esperanza J., 2007).
Immunity to Infection
Most of the microorganisms that manage to evade these barriers and
cause infection are destroyed in a few hours by non-specific
mechanisms of rapid induction. However, if an infectious agent is able
to overcome these first lines of defense, it will activate, in most cases, a
highly specialized and specific type of defense response (Chabalgoity J.
Et. Al., s. f.).
Immunity to Bacterial Infections
The first steps of the classical pathway require the binding of antibodies
to the surface of the bacteria to be destroyed. These antibodies are
recognized by a complement protein complex called C1, which will
bind to the Fc regions of the antibodies. Once it is bound, C1 initiates a
cascade of fragmentation and modification of complement complexes
that results in the binding of various proteins to the surface of bacteria
in the form of a membrane attack complex. or they can generate
opsonins that mark bacteria for destruction. Bacteria can also be killed
by phagocytes (Laing K. s.f).
Immune Response to Viruses
Viruses are obligate intracellular microorganisms that generally enter
susceptible cells using normal cell surface molecules as receptors.
When the virus is inside the host cell, it causes cell injury by different
mechanisms. Viral replication can interfere with cell protein synthesis
and cause cell death by lysis, releasing many new viral particles. The
infection stimulates the production of IFN 1 that helps in the synthesis
of cellular enzymes that interfere with the replication of viral RNA or
DNA, NK lymphocytes kill virus-infected cells and they are an
important mechanism of immunity against viruses early in infection,
before adaptive immune responses develop. Adaptive immunity against
viral infections is mediated by antibodies, which block the binding and
entry of the virus into host cells. (Chabalgoity J. Et. Al., s. f.).
 Background
1. Microbological Information
1.1 Comparative analysis of emergence and spreading of coronaviruses
In 2003, the Chinese population was infected with a virus causing Severe Acute
Respiratory Syndrome (SARS) in Guangdong province. The virus was confirmed as a
member of the Betacoronavirus subgroup and was named SARS-CoV (Peiris et al, s.f). The
infected patients exhibited pneumonia symptoms with a diffused alveolar injury which
lead to acute respiratory distress syndrome (ARDS). SARS initially emerged in Guangdong,
China and then spread rapidly around the globe with more than 8000 infected persons
and 776 deceases. A decade later in 2012, a couple of Saudi Arabian nationals were
diagnosed to be infected with another coronavirus. The detected virus was confirmed as a
member of coronaviruses and named as the Middle East Respiratory Syndrome
Coronavirus (MERS-CoV). The World health organization reported that MERS-coronavirus
infected more than 2428 individuals and 838 deaths (Rahman et al, s.f). MERS-CoV is a
member beta-coronavirus subgroup and phylogenetically diverse from other human-CoV.
The infection of MERS-CoV initiates from a mild upper respiratory injury while progression
leads to severe respiratory disease. Similar to SARS-coronavirus, patients infected with
MERS-coronavirus suffer pneumonia, followed by ARDS and renal failure (Memish et al,
s.f).
Recently, by the end of 2019, The World Health Organization was informed by the Chinese
government about several cases of pneumonia with unfamiliar etiology. The outbreak was
initiated from the Hunan seafood market in Wuhan city of China and rapidly infected more
than 50 people. The live animals are frequently sold at the Hunan seafood market such as
bats, frogs, snakes, birds, marmots and rabbits (Wang et al, s.f). On 12 January 2020, the
National Health Commission of China released further details about the epidemic,
suggested viral pneumonia (Wang et al, s.f). From the sequence-based analysis of isolates
from the patients, the virus was identified as a novel coronavirus. Moreover, the genetic
sequence was also provided for the diagnosis of viral infection. However, further
investigations revealed that some individuals contracted the infection even with no record
of visiting the seafood market. These observations indicated a human to the human
spreading capability of this virus, which was subsequently reported in more than 100
countries in the world. The human to the human spreading of the virus occurs due to close
contact with an infected person, exposed to coughing, sneezing, respiratory droplets or
aerosols. These aerosols can penetrate the human body (lungs) via inhalation through the
nose or mouth (Fig.1) (Phan et al, s.f).
 1.2 Primary reservoirs and hosts of coronaviruses
The source of origination and transmission are important to be determined in order to
Fig. 1The key develop
reservoirs and mode of transmission
preventive strategiesoftocoronaviruses
contain the(suspected reservoirs
infection. of SARS-CoV-2
In the case of are red encircled);
SARS-CoV, the only a and b
coronaviruses have the ability to infect humans, the consumption of infected animal as a source of food is the major cause of animal to
researchers initially focused on raccoon dogs and palm civets as a key reservoir of
human transmission of the virus and due to close contact with an infected person, the virus is further transmitted to healthy persons.
infection.
Dotted black arrow Later
shows the on, Rhinolophus
possibility of viral transferbats
fromwere also found
bat whereas the solidto have
black anti-SARS-CoV
arrow antibodiestransfer.
represents the confirmed
suggesting the bats as a source of viral replication (Shi, s.f). The Middle East respiratory syndrome
(MERS) coronavirus first emerged in 2012 in Saudi Arabia (Memish et al, s.f). MERS-coronavirus
also pertains to beta-coronavirus and having camels as a zoonotic source or primary host (Paden
et al, s.f). In a recent study, MERS-coronavirus was also detected in Pipistrellus and Perimyotis
bats, proffering that bats are the key host and transmitting medium of the virus (Annan et al, s.f).
Initially, a group of researchers suggested snakes be the possible host, however, after genomic
similarity findings of novel coronavirus with SARS-like bat viruses supported the statement that
not snakes but only bats could be the key reservoirs (Table 2) (Lu et al, s.f). Further analysis of
homologous recombination revealed that receptor binding spike glycoprotein of novel coronavirus

Table 2. Comparative analysis of biological features of SARS-CoV and SARS-CoV-2.

is developed from a SARS-CoV (CoVZXC21 or CoVZC45) and a yet unknown Beta-CoV (Chan et
al,s.f).

1.3 Genomic variations in SARS-CoV-2

The genome of the SARS-CoV-2 has been reported over 80% identical to the previous
human coronavirus (SARS-like bat CoV) (Wu et al,s.f). The Structural proteins are
encoded by the four structural genes, including spike (S), envelope (E), membrane (M) and
nucleocapsid (N) genes. The Open Reading Frame 1a (ORF1a) is the largest gene in Severe
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which encodes the pp1ab
protein and 15 nsps. The Open Reading Frame 1a (ORF1a) gene encodes for pp1a protein
which also contains 10 nsps (Wu et al, s.f). According to the evolutionary tree, Severe
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) lies close to the group of
SARS-coronaviruses (Hui et al,s.f). Recent studies have indicated notable variations in
SARS-CoV and SARS-CoV-2 such as the absence of 8a protein and fluctuation in the
number of amino acids in 8b and 3c protein in Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2) (Wu et al, s.f). It is also reported that Spike glycoprotein of
the Wuhan coronavirus is modified via homologous recombination. The spike glycoprotein
of Severe Acute Respiratory Syndrome Coronavirus 2 is the mixture of bat SARS-CoV and
a not known Beta-CoV (Li et al,s.f). In a fluorescent study, it was confirmed that the Severe
Acute Syndrome Coronavirus 2 (SARS-CoV-2) also uses the same Angiotensin Converting
Enzyme 2 (ACE 2) cell receptor and mechanism for the entry to host cell which is
previously used by the SARS-CoV (Gralinski et al, s.f). The single N501T mutation in
Severe Acute Respiratory Syndrome Coronavirus 2’s Spike protein may have significantly
enhanced its binding affinity for ACE2 (Wan et al, s.f).
The HPG axis has been extensively linked with pulmonary and cardiovascular physiology.
Estrogen, progesterone, and testosterone are the three most important sex steroid hormones
impacting these organ systems. Humans express two types of estrogen receptors (ER), ERa
and ERb, and the expression of these receptors varies between organs and cell types.
Estrogen acts via classical receptor-mediated, nonclassical, and non-ligand-mediated
genomic (nuclear) and nongenomic (extranuclear) pathways to control mechanisms of gene
expression, protein modifications and signaling to influence cellular functions. The
endogenous estrogens produced in female mammals exists in three forms, estrone (E1),
17b-estradiol (E2), and estriol (E3); among these, E2 is the most prevalent and functional.
Women as compared with men produce higher levels of estrogen, which results in more
robust innate, humoral, and cellular immune responses mediated by ER signaling. In men,
higher testosterone secretion has an inhibitory effect on the immune system through the
upregulation of IL-10, an anti-inflammatory cytokine (Liva et al, s.f)
The expression of hormone receptors on immune cells facilitates greater response to antigens,
vaccines, and infections in women as compared with men. In contrast, the
testosterone/androgen system is generally less effective at generating immune and
inflammatory responses, which may lead to sexual dimorphism in Severe Acute
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral infectivity (Sumi et al, s.f).
 2. Epidemiology
In early studies, 49–66% patients had the contact history of Huanan seafood market, where
various kinds of living wild animals were on sale, including poultry, bats, and marmots. It
is currently speculated that the outbreak of Coronavirus Disease19 (COVID 19) in Wuhan
is associated with wild animals. According to WHO, the environmental samples taken from
Huanan seafood market were tested positive for Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2), but the specific animals associated with the virus have not
been identified. The RaTG13, which is a short RNA dependent RNA polymerase (RdRp)
region from a bat coronavirus, was closest to Severe Acute Respiratory Coronavirus 2
(SARS-CoV-2) with 96.2–98.7% identity in whole-genome sequence. The other two bat-
derived SARS-like coronaviruses, batSL-CoVZXC21 and bat-SL-CoVZC45, were closer to
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) than SARS-CoVand
MERS-CoV, which have approximately 88% nucleotide identity. As for the intermediate
hosts of SARS-CoV-2, recent studies suggested pangolins were the most probable animal.
Two sub-lineages of Severe Acute Respiratory Syndrome (SARS-CoV-2) were found in
organs of pangolins obtained from anti-smuggling activities in Guangdong and Guangxi
Province of China by metagenomic sequence. Xiao et al. reported the Severe Acute
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was derived from the reorganization
of pangolin-CoV-like virus and a Bat-CoVRaTG13-like virus. However, the pangolin may
not be the only intermediate reservoir, because Severe Acute Respiratory Coronavirus 2
(SARS-CoV-2) was not originated from pangolin-CoV-like virus directly, which was
demonstrated by the molecular and phylogenetic analyses in Liu’s study. (Lam et al, s.f).

3. Vaccines
3.1 What is a Vaccine?
A vaccine is a substance that helps protect against certain diseases. Vaccines contain a dead
or weaken version of microbes, virus or bacteria. It helps immune system to recognize and
destroy the living microbe during a future infection. (Lam et al, s.f).
3.2 Vaccine Development
The development, testing and regulation of vaccines, evolved to the current system in the
1900’s. Development can take many years and if it succeeds, it could end up to a large-
scale vaccination programme. Many of the vaccines fail at the beginning because they are
unsuccessful to produce the desired immune response. [Stages of Vaccine Development, 17
2017.]
Development of every vaccine starts with the exploratory stage. It consists of laboratory
research to identify antigens that might be able to treat or prevent a disease. [Vaccine
Development, Testing, and Regulation, 2018.] The found microorganisms are weaken or
killed so that they cannot replicate and cause a disease anymore. The wanted part of the
microorganism is the most immunogenic part that is used to manufacture a vaccine. In this
way, the patient can develop a better and most efficient immunological reaction.
In the stage of clinical development, the vaccine is tested in humans. The testing takes
place in four phases and can take many years. First three phases are the clinical trials. The
stage of clinical development is based on strict ethical principles. Volunteers are well
informed of the vaccine safety and efficacy. [Stages in Vaccine Development, 2017.]
Phase 1 is performed a in small scale with 20 to 100 healthy volunteers. Its purpose is to
determinate safety and dosage [Lane, s.f.] In Europe, there is phase 1a and 1b. These are for
testing vaccine for the diseases of poverty. Phase 1a is for European volunteers and phase
1b for volunteers in developing countries. [Stages in Vaccine Development, 2017.]
Vaccines that are targeted to children, are first tested with adults. Volunteers in these
studies are attentively monitored and the conditions are controlled. [Vaccine Development,
Testing, and Regulation, 2018.]
Phase 2 is tested with a larger group of 100 to 500 patient volunteers. The purpose of this
phase is to evaluate effectiveness of the vaccine versus clinical diseases and artificial
infections. Immune response, alongside side-effects, are also evaluated and the method of
the delivery is decided. [Stages in Vaccine Development, 2017.] In this phase the trials are
controlled and randomized. A group of people is also having a placebo vaccine in the tests.
[Vaccine Development, Testing, and Regulation, 2018.]
Phase 3 confirms effectiveness and monitors adverse events originating from long term use.
This phase is tested with 1000-5000 patient volunteers to evaluate the effectiveness under
natural disease conditions. [Lane, 2016.] The tests in this phase are randomized and the
developed vaccine is tested against a placebo [Vaccine Development, Testing, and
Regulation, 2018]. If the vaccine is safe and effective for a defined period, can the
manufacturer apply for a license from the regulatory authorities. If the license is admitted,

Fig. 2 Phases of Vaccine Development

can the manufacturer start to market the vaccine for human use. [Stages in Vaccine
Development, 2017.]
Advances in Coronavirus Disease 19 (COVID 19) vaccine
In general, the Th1 type immune response plays a dominant role in an adaptive immunity to viral
infections. Cytokine microenvironment generated by antigen presenting cells dictate the direction
of T cell responses. Helper T cells orchestrate the overall adaptive response, while cytotoxic T cells
are essential in killing of viral infected cells. Humoral immune response, especially production of
neutralizing antibody, plays a protective role by limiting infection at later phase and prevents
reinfection in the future. (Liu WJ. et al, s.f)

SARS-CoV infection induces seroconversion as early as day 4 after onset of disease and was found
in most patients by 14 days. Long lasting specific IgG and neutralizing antibody are reported as
long as 2 years after infection. (Liu W. et al, s.f)

A limited serology details of SARS-CoV-2 was reported. In a preliminary study, one patient showed
peak specific IgM at day 9 after disease onset and the switching to IgG by week 2.25 Interestingly,
sera from 5 patients of confirmed COVID-19 show some cross-reactivity with SARS-CoV, but not
other coronavirus. Furthermore, all sera from patients were able to neutralize SARS-CoV-2 in an in
vitro plaque assay, suggesting a possible successful mounting of the humoral responses. (Zhou P,
et al. s.f)

Due to the rapid increase of SAR-CoV-2 infections and affected countries, efforts toward
developing an effective SARCoV-2 vaccine have been ignited in many countries. The target antigen
selection and vaccine platform are probably based on SARS-CoV and MERS-CoV vaccine studies.
Full-length spike (S) or S1 which contains receptor binding domain (RDB) might be considered as a
good vaccine antigen because it could induce neutralizing antibodies that prevent host cell
attachment and infection. (Al-Amri SS et al, s.f)

Nucleic acid-based vaccine, DNA vaccine, showed the most advance platform in response to
emerging pathogens. Recent mRNA vaccine designs have improved stability and protein
translation efficiency thus it could induce robust immune responses. (Pardi N. et al, s.f)

In order to make SAR-CoV-2 vaccine possible, gathering of important information for vaccine
development and evaluation should be well defined. This includes finding target antigen(s),
immunization route, correlated-immune protection, animal models, scalability, production facility,
target product profile (TPP), outbreak forecasting and target population. In addition, the study of
the immune correlates of protection and the long-term immune memory from convalescent
individuals may help in design prophylactic and therapeutic measures for future outbreak of
similar coronaviruses. (Thomas SJ, et al. s.f)

Problem Statement
Coronavirus disease 2019 (COVID-19) is defined as illness caused by a novel coronavirus
now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; formerly called
2019-nCoV), which was first identified amid an outbreak of respiratory illness cases in
Wuhan City, Hubei Province, China. It was initially reported to the World Health
Organization on December 31, 2019. Months later, it would become the leading cause of
death worldwide.
Currently, several sanitary measures have been implemented around the world to contain its
spread, but none of them have obtained the desired results, giving us more than 30 million
cases until this day.
If the pandemic persists, the world would have to find some way to adapt, giving us an
increase in the number of deaths, infections and a greater number of collapses in hospital
services.
On the other hand, life would change, developing a greater habit of washing hands, wearing
face masks and maintaining a distance of six feet between individuals.
There is only one solution for the future, the development of the vaccine to control the
number of infections and deaths worldwide.

Justification
The project that we present was born as the result of an exhaustive
investigation about the vaccines that are currently being carried out against
COVID 19.
In this way, we will develop an investigation process that will helps us to
disseminate information about the advances of vaccines against COVID 19 to
the medical community.
Once the most important information about vaccines has been obtained, it is
proposed to make a summary with the most relevant and current data so far,
on this topic.
Although there is not much information about its developments, we will seek
to provide the most up-to-date and best quality information to achieve the best
possible conclusion to our objectives.
Aims and Objectives of the study
General Objectives:
To perform a bibliographic investigation about the COVID 19 vaccines that
are being developed.
Specific Objectives:
 Through a deep research, based on the most recent articles published by
medical bibliographic sources.
  To know the results of which are the institutions that have been in
charge of creating the most effective vaccine.
 To investigate the adverse effects that the different vaccines can have.
Methodology
Materials: PubMed, Elsevier, Scielo, Medscape, Redalyc, WHO, Intramed,
Tripdatabase, The Journal of the American Medical Association, The Lancet, NEJM, BMJ.

Methods: From 35 articles, we chose only 12, since the vast majority
contained similar information. Regarding the 12 selected articles, they offered
us different information, which will be helpful in developing this research.
Results
Ensuring Uptake of Vaccines against SARS-CoV-2
As Covid-19 continues to exact a heavy toll, development of a vaccine
appears the most promising means of restoring normalcy to civil life. One
option for increasing vaccine uptake is to require it. Mandatory vaccination
has proven effective in ensuring high childhood immunization rates in many
high-income countries. However, except for influenza vaccination of health
care workers, mandates have not been widely used for adults.

Although a vaccine remains months to years away, developing a policy

strategy to ensure uptake takes time. By the time a vaccine is available, more
will be known about natural immunity in the population, the consequences of
relaxing community mitigation measures, and the feasibility of scaling up test-
and-trace strategies. The supply of vaccine is sufficient to cover the population
groups for which a mandate is being considered. Available evidence about the
safety and efficacy of the vaccine has been transparently communicated.

The state has created infrastructure to provide access to vaccination without

financial or logistic barriers, compensation to workers who have adverse
effects from a required vaccine, and real-time surveillance of vaccine side
effects. In a time-limited evaluation, voluntary uptake of the vaccine among
high-priority groups has fallen short of the level required to prevent epidemic
spread. The second criterion is that the Advisory Committee on Immunization
Practices , after reviewing the safety and efficacy evidence, has recommended
vaccination for the persons who would be covered by a mandate. Currently
available evidence suggests that the elderly, health professionals working in
high-risk situations or working with high-risk patients , and persons with
certain underlying medical conditions may be high-priority groups for the
ACIP’s consideration, along with other workers with frequent, close, on-the-
job contacts and persons living in high-density settings such as prisons and
dormitories.

When a vaccine nears approval, the ACIP should review the updated evidence
and develop recommendations. Only recommended groups should be
considered for a vaccination mandate, though health officials can encourage
voluntary uptake for others, using means such as public education campaigns
and free vaccination. FDA approval reflects a determination that clinical trial
evidence shows that the benefits of a vaccine outweigh its risks. ACIP
recommendations reflect broader considerations, including values and
preferences of affected groups, implementation issues, and health economic
analyses.

The third criterion is that there is an adequate supply of vaccine to cover the
groups for which a mandate is being considered. The fourth criterion is that
there has been transparent communication of the best available evidence about
the vaccine’s safety and efficacy. 4 Particularly given the possibility that the
evidence underlying FDA approval of SARS-CoV-2 vaccines may be more
modest than usual, policymakers and the public will need to understand the
limits of what is known. The fifth criterion is that the government has put in
place certain support mechanisms for persons required to receive the vaccine.

Lessons from past vaccination campaigns suggest that a generous

compensation program for people who have serious vaccine side effects
should be a centerpiece of these efforts. A federal compensation fund like the
Smallpox Vaccine Injury Compensation Program is one attractive
model, although identifying compensable injuries may be challenging with a
novel vaccine. The last criterion is that vaccination mandates are imposed only
after a time-limited trial of voluntary vaccine provision has proved
unsuccessful. Principles of public health ethics support trying less burdensome
policies before moving to more burdensome ones whenever possible.

States should implement a system for measuring vaccine uptake within each
high-priority group against a set of coverage targets. Because the
constitutional power to protect public health rests primarily with states, each
state will need to adopt its own legislation. Proposed legislation should be
supported by attestations from the state health officer, the ACIP, or another
expert committee that all trigger criteria have been met. Targeted SARS-CoV-
2 vaccination mandate policies may also be appropriate in certain federal
contexts, including high-risk groups in active-duty military
environments, Veterans Affairs facilities, federal prisons, and immigration
detention centers.

Although state vaccination mandates are usually tied to school and day care
entry, that approach is not appropriate for SARS-CoV-2 because children
won’t be a high-priority group. Both are bad public health policy for a Covid-
19 vaccine because they may stoke distrust without improving uptake. The
need to build public trust requires that state officials implement vaccination
policy through a transparent and inclusive process, working closely with
stakeholder groups such as local health officers, health professional and
hospital associations, representatives of high-risk population groups, and
groups concerned about vaccine safety. The HPV vaccine manufacturer’s
direct involvement in crafting and lobbying for mandate legislation raised
suspicion that profit rather than public health motives lay behind such
proposals, undercutting support for vaccination even without a mandatory
regime. (Trogen et al., 2020)
SARS-CoV-2 vaccine research and development: conventional vaccines
and biomimetic nanotechnology strategies
It is important to highlight that emerging methods of genetic engineering and
nanotechnology have revolutionized vaccine development. Nanoparticle-based
biomimetic vaccines have become attractive alternative strategies for disease
prevention.
Viral vector vaccine
Viral vector vaccines use live recombinant viruses to deliver DNA to human
cells. The DNA sequences loaded into the viral vector vaccines encode one or
more antigens. After these vector vaccines infect cells, the antigen protein is
expressed on the cells and the antigen is processed to activate the immune
response.
The genes encoding protein N and protein S have been loaded into viral
vectors to trigger anti-coronavirus immunity in the host. these viral vector
vaccines are capable of eliciting a specific CD8 + T cell response and
generating high levels of virus neutralizing antibodies.
The adenovirus type 5 vector is the most widely used vector. The Ad5 vector
vaccines against human immunodeficiency virus type 1 and Ebola virus have
been investigated in phase II clinical trials to verify their safety and efficacy.
However, adenovirus infection induces a strong innate and adaptive immune
response and establishes a long-term immune memory. Therefore, the
immunogenicity and clinical utility of the Ad5 vector vaccine are limited.
Subunit vaccine
A subunit vaccine is a vaccine produced from selected viral antigenic protein
subunits. Therefore, this type of vaccine has a lower risk of adverse reactions
compared to a whole virus vaccine. It is necessary to identify critical
neutralizing epitopes in the MERS-CoV S protein and exclude non-
neutralizing epitopes without the expense of domain integrity and stability in
the design of the subunit vaccine to induce the host immune response.
Nucleic acid vaccine
Nucleic acid vaccines include DNA vaccines and mRNA vaccines. DNA
vaccines are based on bacterial plasmid vectors that encode vaccine antigens
driven by efficient eukaryotic promoters. The application of a DNA vaccine
encoding the S protein of the MERS virus has been successful in the phase I
clinical trial. Vaccine-induced humoral and cellular responses have been
detected in the testing.
The mRNA vaccine aims to deliver mRNA encoding antigens on the ribosome
to produce viral antigens. The mRNA vaccine is taken up by different cell
types and activates the immune system through the MHC-Ⅰ pathway and the
MHC-Ⅱ pathway after vaccination. When the APCs take the mRNA vaccine,
the APCs process and express the target protein as an endogenous antigen, and
then activate CD8 + T cells through the MHC-Ⅰ pathway. When the mRNA
vaccine is taken up by non-APC, the cells translate and secrete the target
protein which is then taken up by APC. Subsequently, APCs activate CD4 + T
cells through the MHC-Ⅱ pathway.
MRNA-1273 is a vaccine that encodes a prefusion stabilized form of the S
protein of SARS-CoV-2.
Biomimetic Nanotechnology in Vaccine Development
Biomimetic nanoparticles have unique antigenic characteristics and
immunostimulatory properties and have been used to design more effective
vaccine formulations. MERS-CoV-specific memory CD8 + T cells can be
detected in the body for up to 6 years and perform a strong antiviral effect on
various virus subtypes. Live attenuated vaccines are capable of inducing the
formation of memory T cells. However, the potential risk of restoration of
virulence makes it difficult to apply conventional coronavirus vaccines in
clinical trials.
VLP vaccines are considered a powerful candidate for the prevention of the
SARS-CoV-2 pandemic. However, to date, few studies have investigated
whether combining VLP with adjuvants improved the protective effects of
VLP-based vaccines. A research team uses its proprietary recombinant protein
nanoparticle technology platform to develop a SARS-CoV-2 candidate
vaccine containing the coronavirus protein S. They recommend using their
proprietary Matrix-M ™ adjuvant to enhance immune responses during
vaccination with the vaccine.
Summary of Advances in COVID-19 Vaccine Development
In February 2020, the World Health Organization convened researchers
worldwide to define the research agenda for drugs and vaccines against
SARS-CoV2, through the Global Initiative for Research and Development.
The intention is to have some candidate vaccines that can be submitted to
regulatory authorities for approval for general use or for use in outbreak
situations.
The three vaccines that as of April 3, 2020, are in a Phase I clinical trial are
briefly described below:
1) Company: Moderna of Cambridge, Massachusetts in collaboration
with the NIAID (National Institute of Allergy and Infectious
Diseases (NIAID).
Name of the candidate vaccine: mRNA-1273, developed based on previous
studies with SARS and MERS.
Description: It uses a synthetic chain of messenger RNA (mRNA), designed
for cells to produce antibodies against the virus.
Study design: Phase 1, open label, use of different doses in 45 healthy adult
volunteers aged 18-55 years.
Status: On March 16, the recruitment process began, and it was completed on
March 19. The study evaluates different doses of the experimental vaccine
from the point of view of safety and immunogenicity. Moderna has indicated
that the vaccine could be commercially available in the United States in 12-18
months, although it has already applied for an emergency use permit that
could allow its use before it is licensed.
2) Company: CanSino Biological Inc. and Beijing China Institute of
Biotechnology
Name of the candidate vaccine: Ad5-nCoV
Description: Uses the same platform used for Ebola (adenovirus viral vector).
His approach is based on taking a fragment of the genetic code of the
coronavirus and intertwining it with a harmless virus, the viral vector of
adenovirus.
Study design: Phase 1, 108 participants between 18 and 60 years who will
receive low, medium and high doses of vaccine.
Status: Recruitment has started. The study will evaluate safety and
tolerability.
3) Company: Oxford University
Candidate Vaccine Name: ChAdOx1
Description: A team of researchers from the Jenner Institute at the University
of Oxford, who had been working on vaccines against MERS, quickly adapted
the technology to produce a vaccine against the new coronavirus SARS-CoV-
2.
Study design: Phase 1, 510 healthy adult volunteers aged 18 to 55 years.
Basic Requirements for a COVID 19 Vaccine
An ideal vaccine against COVID-19 should meet the following requirements:
 Effective with one or two doses.
  Protection in priority population groups: age over 65 years, people with
comorbidities and immunosuppressed.
 Duration of protection of at least 6 months.
 Capable of reducing community transmission of infection.
 Susceptible to be produced on a large scale at an affordable cost and in
a limited time.
Products in More Advanced Clinical Investigation Phases
• Four products have started phase 3 studies: two inactivated vaccines, one of
them adjuvanted with aluminum, ChAdOx1 (AZD1222) and mRNA-1273
• Three products have shown results of the investigations in phases 1 and 2:
ChAdOx1 (AZD1222), Ad5-COVID-19 vectors and mRNA-1273.
Oxford University Vaccine Candidate (CHADOX1, AZD 1222)
ChAdOx1 (AZD1222), chimpanzee adenovirus that expresses the SARS-
CoV-2 protein S.
Results:
 More frequent local and systemic reactions in the intervention group
with ChAdOx1: pain, fever, cold, headache, myalgia, malaise.
 56 in the intervention group and 57 in the control group received
paracetamol (1 g every 6 hours, 4 doses). Paracetamol significantly
reduced reactogenicity in the 48 h after the vaccine.
 No serious adverse effects.
Cell response:
 Peak on day 14 (n = 43): average 856 colony-forming cells per million
mononuclear cells in peripheral blood (interquartile range: 493-1802).
The response remained unchanged until day 56, even in those who
received a booster dose.
Humoral response:
 Peak on day 28 (n = 127): IgG anti protein S 157 UI Elisa (96-317).
Day 56, after booster dose (n = 10): 639 IU (360-792).
 Day 28 (n = 35): neutralizing antibodies (MNA 80 and PRNT50) 91-
100%. Day 56, after booster dose (n = 10): 100%.
Limitations:
 Short follow-up time.
 Low number of participants in the subgroup that received a booster
dose.
 Participants without social representation; most of them were healthy
white young adults.
COVID-19: Russia Approves Vaccine Without Large Scale Testing Or
Published Results
Russia approved a vaccine that was only subjected to a phase I trial, with 38
people without published results, this was announced by Vladimir Putin,
where he claimed that one of his daughters had received it. In August, phase
III trials began, which would involve people from Russia, Saudi Arabia and
the United Arab Emirates.
Within the trials, there are currently 165 candidates around the world. Russia
has developed the vaccine by the Gamaleya Institute in Moscow, using two
adenovirus vectors. In new trials, it was reported that 9 patients received this
vaccine recombined with human adenovirus type 26. The record stated that
patients would be followed for four visits, performed seven, 14, 28 and 42
days after drug administration and again at 90 and 180 days.
Currently the vaccine in development is known as "Sputnik V".
Discussion: Although to date there is no definitive vaccine, there are several
investigations and experiments being carried out, despite the fact that various
authors do not publish more information due to the informed consent signed
by the participants, thanks to this, it is saved the identity of the participant and
various aspects that could be of great help to analyze why various
investigations of the vaccine have not been able to advance. On the other
hand, there are various limitations in these studies such as time, this is
summarized in science against time, the later the vaccine, the more lives will
be lost.
However, thanks to these studies and publications, we have managed to learn
about the behavior of the virus, its mechanism of action and transmission for
the implementation of adequate hygiene measures.
Conclusion: In conclusion, we were able to realize the long process involved
in developing the vaccine, and that it is still uncertain when it will be released
to the general public. Despite the time it may take, the effectiveness is
uncertain as is its safety. Although to date there are almost 10 vaccines in
possible development, none of these have given good results in phase 3, which
indicates that there is still a long way to obtain it.
Acknowledgments:
In the elaboration of this project, students from different semesters
participated working really hard, who directly contributed the labor, Dr. Ana
Gabriela Martínez Ramos, who guided us throughout this project. Without
her this work would not have been possible. We also thank Dr. José Antonio
Luna Roldán, who kindly shared the most recent articles about COVID 19
vaccines, helping us to expand the research.

References
Trogen B, Oshinsky D, Caplan A. Adverse consequences of rushing a SARS-
CoV-2 vaccine: implications for public trust. JAMA 2020;323:2460-2461.