Vaccines to combat Coronavirus (SARS-CoV-2)

According to the Pan American Health Organization, coronaviruses (CoV) are a large family of viruses that can cause a variety of conditions, from the common cold to more serious illnesses, such as the coronavirus that causes Middle East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV). A novel coronavirus (CoV) is a new strain of coronavirus that has not previously been identified in humans. The new coronavirus, now known  as2019-nCoV or COVID-19, had not been detected before the outbreak was reported in Wuhan, China, in December 2019.

Coronaviruses can be transmitted from animals to humans (zoonotic transmission). Based on extensive studies, we know that SARS-CoV was transmitted from civet to humans and that there has been transmission of MERS-CoV from dromedary camels to humans. In addition, other coronaviruses are known to be circulating among animals, but have not yet infected humans.

According to the World Health Organization; Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. Most people infected with the virus will experience mild to moderate respiratory illness and recover without requiring special treatment. However, some will become severely ill and require medical attention. Older people and those with underlying illnesses, such as cardiovascular disease, diabetes, chronic respiratory disease or cancer, are more likely to develop severe illness. Anyone, of any age, can contract COVID-19 and become seriously ill or die.

According to the global data and business intelligence platform known as Statista; as of August 2, 2023, about 769 million cases of coronavirus (SARS-CoV-2) have been reported worldwide (See graph below). The coronavirus that originated in the Chinese city of Wuhan has spread to all countries in Europe and the world.

On the same global platform; the statistic shows the number of deaths caused by SARS-CoV-2, worldwide as of August 8, 2023. As of that day, approximately seven million deaths due to the virus had been counted, of which 5,272 occurred in China, the place where the virus originated. However, the Asian country is no longer the territory where the new coronavirus has claimed the most lives. The United States leads the ranking with close to 1.2 million deaths, followed by Brazil with around 704,795 deaths.

The best way to prevent and slow transmission is to be well informed about the disease and how the virus is spread. Protect yourself and others from infection by staying at least one meter away from others, wearing a tight-fitting mask, and washing your hands or cleaning them with an alcohol-based hand sanitizer frequently. Get vaccinated when it is your turn and follow local guidelines.

The virus can spread from the mouth or nose of an infected person in small liquid particles when coughing, sneezing, talking, singing or breathing. These particles range from larger respiratory droplets to the smallest aerosols. It is important to adopt good breathing practices, for example, coughing into the inside of a flexed elbow, and to stay home and self-isolate until you recover if you feel unwell.

Our company has chosen to work on the development of vaccines based on antigens (proteins, molecules or segments of molecules), which are produced by the intestinal microbiota (bacteria of the human intestine) and have the ability to eliminate viruses, these antigens are tolerated by the human body.

Our vaccine is based on a line of research developed over the years that formalizes the finding of the existence of a mutualistic relationship between human beings and the intestinal microbiota that not only benefits man with the assimilation and degradation of nutrients that belong to the food that enters the digestive tract, but also allows it to deploy and play an outstanding role as an additional organ that contributes to the improvement and diversity in the capacity of the innate and adaptive immune response of our species.

Our vaccine will be obtained from antigens (Any protein or molecule) of the tolerogenic type secreted by the intestinal microbiota of patients with covid-19 who are asymptomatic or who do not develop the disease or only have mild symptoms of it, the candidate bacteria to be selected to obtain these antigens will be identified with the help of Artificial Intelligence software trained with parameters determined in previous research reported in the specialized literature.

The tolerogens obtained in principle will be substances that by their molecular structure can activate or catalyze an immune response in the individual and may also possess the ability to combat pathogens (specifically viruses) through chemical, biochemical and physiological processes, among which may be mentioned:

i. Tolerogens with the property of degrading the virus envelope in such a way as to strip it and expose the proteins present in its capsid; which would imply facilitating the activation and action of the cells of the innate and adaptive immune system to eliminate the pathogen.

ii. Tolerogens with the property of degrading the virus capsid so as to unprotect the viral genome; which would imply facilitating the activation and action of the cells of both the innate and adaptive immune system to eliminate the pathogen.

iii. Tolerogens that perform (after crossing the viral capsid or envelope) a function equivalent to the action of nucleases that affect and destroy the viral genome.

iv. Tolerogens that perform the function of inhibiting viral glycoproteins and preventing viral infectivity.

v. Tolerogens capable of interfering with the binding of viral particles to host cell membranes.

vi. Tolerogens capable of inhibiting a cellular receptor or factor required for viral replication.

vii. Tolerogens that block specific virus-encoded enzymes and proteins that are produced in host cells and are essential for viral replication but not for normal host cell metabolism.

viii. Tolerogens that act in a manner similar to interferons and result in the arrest of viral replication without compromising normal host cell function.

ix. Tolerogens with adjuvant properties that activate and catalyze antigen-presenting cells of the immune system to enhance immunogenicity, generating a kind of self-vaccination process in the host.

x. Tolerogens with antibody-equivalent properties.

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According to the United Nations; By 2022; two years after the outbreak of the coronavirus, the global response has only highlighted the differences between rich and poor countries, and within countries themselves among the most vulnerable, a study by the UN development agency shows. Inequity in vaccines, in addition to prolonging the pandemic, slowed the economic recovery of entire countries and jeopardized global labor markets, public debt payments and the ability of countries to invest in other priorities.

In a new study released this month, the United Nations Development Programme (UNDP) shows that only a tiny proportion of COVID-19 vaccines have been administered in developing countries, leading to a widening gap between rich and poor countries. In September 2021, the World Health Organization (WHO) set the ambitious global target of vaccinating 70% of the global population by mid-2022. At that time, just over 3% of people in low-income countries had been vaccinated with at least one dose, compared to 60.18% in high-income countries. Six months later, the world is nowhere near the target.

The total number of vaccines administered has increased enormously, but so has the inequity in their distribution: of the 10.7 billion doses delivered worldwide, only 1% have reached low-income countries. This means that 2.8 billion people worldwide are still waiting to receive their first vaccine. Inequity in vaccination jeopardizes the safety of all and is largely responsible for the growing inequalities both between and within countries.

By 2022; two years after the outbreak of the COVID-19 pandemic, the poorest countries were finding it harder than ever to recover economically, labor markets are suffering, public debt remains persistently high and there is little left in the coffers to invest in other priorities. The United Nations Development Programme  study shows that most of the most vulnerable countries in terms of COVID-19 vaccination are in sub-Saharan Africa, such as Burundi, the Democratic Republic of Congo and Chad, where less than 1% of the population has received the full immunization schedule. Outside Africa, Haiti and Yemen have not yet reached 2% coverage.

All viruses change over time, and this includes the virus that causes COVID-19. ". Equal access to a COVID-19 vaccine is the key to defeating new variants of the SARS-CoV-2 virus with the capacity to generate a new and deadly spike in cases, which will challenge healthcare systems worldwide. This cannot be a race in which only a few win, and that is why once our vaccine is developed and validated, we will not affiliate to the COVAX Mechanism, which is an important component of the solution, as it ensures that all countries can benefit from access to the largest portfolio of candidates in the world and from a fair and equitable distribution of vaccine doses.

Adherence to the COVAX Mechanism gives all countries the best opportunity to protect the most vulnerable members of their populations, which in turn gives the world the best opportunity to mitigate the consequences of this pandemic for individuals, societies and the global economy.

During the last 20 years our vaccine proposal has gone through stages of maturation and development; although the Covid-19 disease pandemic started at the end of 2019 in the Chinese city of Wuhan, our initial target (and the one we are still working on) was viruses associated with chronic viral infections characterized by continuous, prolonged viral shedding; examples are congenital rubella virus infection or persistent hepatitis B or C.

Due to economic reasons and capacity of execution of our goals, we have always developed our tests and studies, focusing on level 2 biosafety practices, which are applicable to clinical, diagnostic and teaching laboratories and in facilities where broad-spectrum microorganisms of moderate risk, present in the community and associated with human diseases of varying severity, are handled. Hepatitis B virus is a representative microorganism of this containment level.

Over many years, international scientific research has identified several hundred different viruses capable of infecting humans. Viruses that primarily infect humans are usually spread by the respiratory route and by enteric excretions. Blood collected for transfusion is screened for several. Many viruses are transmitted by rodent or arthropod vectors, and bats have recently been identified as hosts for many mammalian viruses, including some responsible for certain serious human infections (e.g., SARS-CoV-2). Given the immense health emergency caused by the Covid-19 pandemic and its marked social and economic consequences, we thought it appropriate to direct all the experience and knowledge accumulated and developed so far towards the combat and containment of the new SARS-CoV-2 pathogen.

On the other hand, our company for years among its many advances has managed to specialize in the area of programming and software development; we have worked in programming areas ranging from computer programs for control and use of electronic and robotic interfaces, to the development of educational and interactive software for use and entertainment on the user's computer.

To learn more see the link: https://youtu.be/1LkntBrSF-g

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This experience has allowed us to develop our own machine learning algorithm capable of detecting alternatives to antibiotics among drugs with other uses. The intestinal microbiota with its 100 trillion microorganisms and more than 5,000 species of bacteria, implies a complex system with millions of variables to consider, which is why Artificial Intelligence is required, using algorithms and mathematical models to process large amounts of data and make decisions based on patterns and rules established through machine learning, which is the ability of a machine to learn autonomously from data without being specifically programmed to do so. In this way AI can improve its accuracy and efficiency over time.

Specifically, the artificial intelligence we are developing is aimed, among other variants, at image analysis software, search engines or systems for the recognition of the bacteria to be studied through the observation of microscopic samples obtained from commercial intestinal microbiota tests, so that the algorithms detect and classify the bacteria based on characteristics that are helpful for bacterial identification, such as: size, morphology and types of groupings.

Intestinal flora or microbiota is the group of bacteria that live in the intestine, in a symbiotic relationship of both commensal and mutualistic type. This group is part of the normal microbiota. The great majority of these bacteria are not harmful to health and many are beneficial, so this intestinal microbiota is important for the health of the organism. It is estimated that humans have about two thousand different bacterial species within them, of which only one hundred can be harmful.1 Many animal species are very closely dependent on their intestinal flora. For example, without it, cows would not be able to digest cellulose, nor termites to feed on wood, since it is not they themselves, but their intestinal flora, that are capable of processing this type of food. In humans, the dependence is not so radical, but it is important.

Sometimes they help in the absorption of nutrients and form a complex ecosystem that regulates itself and keeps itself in balance. On other occasions they are essential for the synthesis of certain compounds, such as vitamin K and some of the B complex. They also have side effects, such as the production of gases, responsible for the characteristic odor of feces. Some of them can cause infections of any severity. The adult flora is influenced by a series of intrinsic (intestinal secretions) and extrinsic (aging, diet, stress, antibiotics and foods with prebiotic components or with probiotic organisms) factors. It regenerates periodically, excreting the dead microorganisms through the feces.

the intestinal microbiota comprises 100 trillion microorganisms, within which there are at least 6,000 species of bacteria. These have about 3 million genes. The gut microbiota can weigh up to two kilograms. Only one third of the microbiota is common among humans. The remaining two thirds are specific to each individual. The Human Microbiome Project has identified only 30% of the gut microbiota. Alterations in the microbiota are called "dysbiosis" and are associated with various diseases. Currently, many scientists around the world are working to decipher the genome of the microbiota and to understand the extent of the influence of this new organ.

From a technological point of view we can guarantee that we already have artificial intelligence software mature enough to tackle the immense task of selecting candidate bacteria in a relatively short time (two months) compared to traditional techniques that would take years or decades to subsequently perform biochemical studies on culture samples to obtain tolerogens that can play the role of vaccine candidates for the so-called preclinical studies, the aim of which is to collect a series of preliminary data that will be applied in subsequent phases. These studies are carried out on animals, generally starting with small mammals with a fast reproduction cycle, such as rodents, and then moving on to larger animals, such as pigs or primates. This activity will be carried out in alliance with specialized laboratories in the world which have been formally selected and with which we are in talks for this purpose.

The great danger of the coronavirus lies in the loss of control due to its relentless transmissibility. Especially by people who do not show respiratory symptoms or fever, so they do not know if they are infected: the so-called "silent" transmitters. Gastrointestinal symptoms can play a key role in stopping the spread. Several phases take place in the course of COVID-19. Sixty percent of those infected were found to have intestinal problems such as diarrhea, vomiting or abdominal pain in the early stages of the disease. This was days before respiratory symptoms or even pneumonia were detected. When infected persons present with intestinal symptoms, coronavirus infection is not suspected. Therefore, they are not tested. This represents a huge risk factor in transmissibility.

At the onset of the disease, the virus begins to replicate and infect cells of different body systems. This can cause intestinal dysfunction, changes in the bacterial flora and acute systemic inflammation. As the disease progresses, the virus does not need to replicate and the most potent inflammatory cascade breaks out, accompanied by respiratory problems and fever. People who presented with intestinal symptoms in the early stages were the ones who developed the most complications in later stages.

The reasons why SARS-CoV-2 causes more pathology in some people than in others remain unknown. Even so, there are patients who manage to clear the virus without developing symptoms, suggesting that a strengthened immune system may hold the key to understanding and overcoming viral infection. In this context, identifying non-respiratory symptoms associated with COVID-19 as early as possible could stop the spread.

The main gateway for SARS-CoV-2 invasion is the angiotensin-converting enzyme 2 (ACE2) receptors that are expressed in the lungs, but are also found in the intestines. Coronavirus entry results in increased inflammation that causes alterations in the intestinal flora. These can aggravate the so-called systemic cytokine storm or hyperinflammation in the most severe patients. Most Covid-19 comorbidities such as obesity, hypertension, cardiovascular disease, diabetes and old age are associated with decreased microbial diversity.

As for Covid-19 studies show that the entry of coronavirus produces an increase in inflammation that causes alterations in the intestinal flora. The lower the diversity of bacteria in the intestinal microbiota, the greater the inflammatory response. Therefore, we would expect a worse prognosis of COVID-19.If we can identify which bacteria orchestrate the course of the disease we might be able to predict the severity and prognosis of COVID-19.  A couple of studies with a very small group of hospitalized patients identified that coronavirus altered patients' gut microbes in relation to the severity of COVID-19. Similar studies are also needed in the asymptomatic or mildly symptomatic population. To identify which intestinal bacteria in SARS-CoV-2 infected individuals are associated with inflammatory markers and viral load. If we can establish which bacteria are associated with symptomatology, we could interfere and modify the abundance of these bacteria to protect against the severity of COVID-19.

Microorganisms inhabit the human intestine mediating the metabolic, physiological and immune functions of the host. Therefore disturbances in this symbiont ecosystem can lead to some diseases. In addition, disease states cause secondary changes in the gut microbiota. Knowledge of all the factors that determine the composition of the microbiota in healthy conditions is essential to decipher the nature of disease states and the development of therapeutic strategies against them. The intestinal microbiota has been associated by several studies to functions such as the metabolism of some carbohydrates, specialization of the immune system and control of the growth of endothelial cells especially of the colon (colonocytes). This last function is very important for the control of cancer in this area, since the bacteria, when metabolizing foods rich in fiber, release butyric acid that is involved in the differentiation of the cells of the large intestine and induces apoptosis, which is important to eliminate non-functional cells that may be cancerous and to mitigate inflammation.

Gut bacteria sense and degrade certain specific polysaccharides of the plant cell wall by means of specific membrane protein complexes, thus enhancing human digestive capabilities. Some types of bacteria possess an arsenal of enzymes for the digestion of complex carbohydrates such as cellulose, hemicellulose and pectin that form plant cell walls. Bacteria break these complex carbohydrates into simple sugars, which are in turn fermented to create short-chain fatty acids that human cells can then use to make the fatty acids.

Functions associated with intestinal flora Carbohydrate metabolism. Micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. These short fatty acids contribute 10% of the calories required by the human body. Polysaccharides such as starch, oligosaccharides and some sugars that are not absorbed by the body during metabolism are digested by the various bacteria in the intestine. As a consequence of this carbohydrate metabolism and its fermentation, gas and flatulence with characteristic fecal odors are produced.

The intestinal flora plays an important role in the specialization of the lymphoid tissue associated with the mucosa of the intestine. These bacteria are responsible for showing lymphocytes (specifically T lymphocytes) which strains are useful to the body and which ones allow them to better recognize invading antigens. In this way, the bacteria housed in the intestine specialize the immune system to favor their survival, which decides which bacteria will be the predominant ones in the microbiota. This is one of the reasons why neonates must be very carefully nourished, since the first bacteria that lodge in the intestine will adapt their microenvironment to favor their own survival, and this could affect the implantation of other essential bacteria in the normal human microbiota.

On the other hand, the intestinal ecosystem is made up of three main components in permanent contact and with complex interactions: host cells, intestinal bacteria and nutrients. Most of the microflora do not adhere directly to the wall, but live in biofilms associated with food particles, mucus or exfoliated cells.

Mucus lubricates and protects the intestinal epithelium from bacteria and the action of digestion. It is composed of mucins capable of selectively or indiscriminately trapping bacteria. The mucin polymers that constitute the mucus contain glycoproteins, the carbohydrate portion of which consists of traces of different sugars: fucose, galactose, N-acetylglucosamine, N-acetylgalactosamine and sialic acid. This carbohydrate portion serves as a nutrient for the microflora, but also as a receptor for microbial toxins and as a surface protein. There is individual genetic control of this carbohydrate repertoire and it is one of the ways by which host genes can utilize the behavior of intestinal microbes.

The immune system of healthy individuals is highly activated in response to dietary antigens, pathogens and normal flora. This results in highly activated Peyer's patch lymphocytes, an abundance of CD8+ T cells in the epithelium and CD4+ T and IgA plasma cells in the lamina propria. Data from animal studies make it clear that it is the normal flora that triggers this response, not pathogens or food antigens. Studies on the mucosal immune system of newborns allow conclusions similar to those obtained from studies with germ-free animals. At birth there are already Peyer's patches, but they have only primary B-cell follicles. Germinal centers appear after a few weeks. The number of intraepithelial lymphocytes is low at birth, but reaches normal values within a few months, especially those of the αβ subclasses. IgA plasma cells are absent at birth, but increase in the first year of life; also in normal individuals the bacteria in the feces are coated with IgA.

The host is isolated and protected from potentially toxic intestinal contents by a unique layer of intestinal epithelial cells. The collaboration between commensal bacteria and the intestinal epithelium helps to create a complex ecosystem, with modification of the cell biology of the host epithelium. A characteristic of this relationship is that a response occurs against enteropathogenic organisms, whereas it does not occur against microorganisms of the indigenous flora. The ultimate mechanism is not known. In circumstances of chronic intestinal inflammation, as occurs in IBD, this homeostasis may break down and agents of the usual microbial flora may become pathogenic. The combined action of a series of receptors present in the extracellular membrane known as toll-like receptors (TLRs) and a family of intracellular protein sensors(nucleotide-binding oligomerization domain/ caspase recruitment domain [NOD/ CARD] is required to detect microbial molecular signals and for the induction of the immune response aimed at maintaining or restoring homeostasis in the host. There are more than 10 TLRs and more than 20 NODs, of which the specific ligand is known for only a few. In recent years it has been discovered that also commensal bacteria act by activating these TLRs, and that this interaction is necessary to maintain the structural integrity of the intestinal mucosa. Many questions remain to be answered: What is the physiological impact of TLR activation by non-pathogenic bacteria? Which TLR-dependent activation pathways and genes are involved in intestinal homeostasis and, conversely, which ones promote intestinal inflammation?

Finally, the intestinal immune system, also known as gut-associated lymphoid tissue (GALT), is responsible for processing antigens that interact with the intestinal mucosa and for disseminating the immune response. There are two separate compartments in the GALT: the inductive sites, where the immune response is initiated after stimulation by an antigen, and the effective sites, which are responsible for executing and terminating the immune response. Peyer's patches would be inductive sites, whereas the intestinal epithelium would behave as an effective site. In addition to the lymphocytes of Peyer's plaques (B-2 cells) there are other peritoneal lymphocytes (B-1 cells) that have inductive action. In the intestinal mucosa two types of lymphocyte populations are distinguished: a) lymphocytes of the lamina propria, and b) intraepithelial lymphocytes, located between the enterocytes along the villi.

Antibody synthesis requires the cooperation of three cell lines. Antigen presenting cells (dendritic cells, B cells and macrophages) are able to capture the antigen, digest it and present it to Th cells. Activated Th cells act on B cells by means of excreted cytokines. Depending on the type of signal, the B cell produces a type of antibody (immunoglobulin [Ig] G, IgA or IgE).There are several types of Th cells that are differentiated according to the cytokine profile excreted. Th1 cells primarily produce interferon alpha (IFN-α) and lead to ineffective antibody production by the B cell (IgG2). Th1 cells are primarily involved in cell-mediated immunity. In contrast, Th2 cells secrete a different type of cytokines that directly influence antibody production by the B cell (IgG1). The two populations are mutually exclusive. The differentiation of T lymphocytes to Th1 or Th2 depends on specific signals. Thus, macrophages and dendritic cells are involved in Th0 to Th1 differentiation by IL-12 and cytolytic lymphocytes perform their role by producing IFN-α.To avoid fetal rejection during pregnancy, the fetus is maintained in a Th2 context and must develop Th1 after birth. The mechanism that triggers this switch is unknown, although intestinal bacteria may be an important factor. Failure to make this switch to Th1 in the neonatal period can lead to allergy problems.

Unlike other mucosa, the intestinal immune system has to distinguish not only between self and non-self, but also between dangerous foreign antigens and food antigens and respond accordingly. Exactly how this mechanism develops is not known, but in part it involves the careful selection of appropriate lymphocyte populations and cytokine expression. The important role of secretory IgA in the exclusion of antigens from the intestinal lumen must also be considered. These features indicate that the development and expression of the intestinal immune system differs greatly from systemic immunity.

Our company wishes to continue this research to finally obtain vaccine candidates in order to move on to the 4 phases of clinical development; to determine if the drug or vaccines are suitable for distribution. In contrast, the fourth and final phase evaluates the actual efficacy of the vaccine or drug on a large number of people vaccinated or treated with the drug. In each phase the product must receive, from the competent health authority, the approval of the results presented before advancing to the next phase. That is why we want to incorporate the Best University in the World, the Massachusetts Institute of Technology; its great human talent and technological and research capacity to help accelerate, concretize and coordinate all the initiatives necessary to achieve the goals that will allow us to successfully reach and complete the 4 phases of the clinical development of our vaccine candidates.

We also hope that by participating in MIT Solve, this prestigious award will value the significant impact of our initiatives, visualizing the positive changes of our solution for people and their communities. We are aware of the significant financial investments required to obtain our vaccines so we hope that MIT Solve will open doors for our solution to receive collaborations, partnerships and additional funding from various stakeholders such as investors, philanthropists and organizations (public and private).