Abstract
We are in a society where news travels like wildfire. The COVID-19 pandemic has forced us to reorder our space and time. This article analyses these changes and puts the human race in the face of possible pandemics that are to come. Nowadays, we live in a world outside the normality to which we want to return as soon as possible. Reality shows that many things have changed, and we do not know very well if they are to stay. Concern for health workers has grown in all countries, their great need has been shown in cases like this, and the worst thing is that according to the statistics, the world will be subjected to pandemics of this kind in the coming years. Finding a vaccine or drug capable of fighting, stopping and defeating it is a challenge for the world in general, and science and scientists in particular. This study also shows the struggle of the best scientific centres, and the different paths they have taken, to reach the goal first. Cooperation between all health agencies has become a priority, now more than ever, efforts are being made to achieve the same goal, to get the COVID-19 vaccine. Let us hope that science has arguments to win this battle, the war is still to come.
Introduction
We are all aware that about four months ago everything worked differently than it does today. Some people have not yet reflected enough on what has happened, and why not venture to say, it will continue to happen; this is not yet over. The world has changed in many things, and these changes have been very noticeable, in such important structures of society as social and health. Healthcare workers have been heroes, fighting bravely against all odds, exposing themselves to infection without protective equipment and working tirelessly to bring infected people forward (Yan et al., 2020; Zou et al., 2020).
The world of information and news has allowed society to keep up with the evolution of the pandemic that is happening to us at the moment through the evolution of the coronavirus COVID-19. On the contrary, there has also been a lot of infotoxication, mainly due to the excessive use of social networks to which all users are exposed and use worldwide.
The information has had to be filtered, and at times, it has been us who, at certain moments, almost out of desperation, have changed a certain piece of news according to our convenience, probably trying not to fall into discouragement in the face of the events of the new pandemic. Its rapid expansion due to the number of infections has led us to situations of overflow as has happened in many health centres and retirement homes, taking measures that we would never have thought of. We are talking about a virus that does not discriminate by gender, sex, ideology, territory, cultural level, religion, and so on, we are talking about a virus that has been able to take humanity almost against the ropes in some moments (Gorbalenya et al., 2020; Guan et al., 2020; Heimdal et al., 2019; Meyer & Christie, 2013).
The confinement of the population has achieved positive things, since by reducing the use of vehicles, the rates of environmental pollution in the cities have been reduced, even if only temporarily, and the ties within the family nucleus have also increased, however, there have also been situations of stress and loneliness in part of the population (Sanglier et al., 2020a).
The pandemic has forced us to reorder our time, to slow down, perhaps this is also a good thing. We are responsible for the education of children who have also been forced to change their habits. The way of working has been changed and teleworking has been incorporated to a greater extent, perhaps with it human relations with friends and family, in the long term, being more impaired (CDC, 2020). But you learn to value more what you do not have.
Society, in general, has had more time to think collectively, to respect confinement measures for a common good, to work together on the issue of opening borders between different countries, to be able to identify transit zones between their communities and to take care to keep the infected persons identified so that the effect on the population is as small as possible.
Each affected country has implemented the measures it has deemed most appropriate, there have been many countries affected in Europe, after the infection started in China (Wu et al., 2020a, 2020), now those countries are recovering, and the infection has advanced to other continents in an alarming way such as Latin America and South Asia. The numbers of people infected and killed by the pandemic are soaring in these areas.
SARS, or severe acute respiratory syndrome, killed 774 people in 17 countries. These outbreaks had mortality rates of 9.5% and 34.5%, respectively (Ding et al., 2003; Li, 2005; Peng et al., 2006). The coronavirus that started in Wuhan has so far caused a number of people infected with COVID-19 worldwide of about 7.5 million people, and a number of deaths of about 420,000 people. Currently, there are about 188 countries out of 194 infected, which means a level of infection of 96.9% of all countries in the world. The countries most affected by the pandemic so far are the United States, Spain, the United Kingdom, Italy, France, Germany, Russia, Turkey and Brazil, where the number of deaths has exceeded 100,000 (WHO, 2020).
It is time to reflect and join efforts in the same direction, to connect, to think logically, to feel, to reflect and to forget values in order to achieve a common goal, to get a vaccine as soon as possible and to put the virus against the ropes, before the virus puts us (Scagnolari et al., 2004; Tian et al., 2020). It is a battle against time, a battle that we can and will win, but as a rule and according to the data of the last few decades, it seems that every four or five years there are outbreaks of viruses that we may not be able to defeat in time, humanity is at stake, and time is golden now, let us make our way little by little but lay the foundations for a future that tends to be very dangerous. Perhaps we have realised that investing in science is investing in a safer future, a future from which a more promising and committed world can be glimpsed. Now it is time to find the saving vaccine that will make us return to the new normality of life, perhaps never again, but it is better than never returning to anything (Chen et al., 2004; Chu et al., 2018; Hoffmann et al., 2020; Morgenstern et al., 2005; Ng et al., 2008; Yang et al., 2004).
Methods and Materials
A study will be conducted on how the different developments of COVID-19 vaccines are going in the countries that are at the forefront of their development. It could be said that almost from the initial moment of detection of this pandemic, different laboratories around the world have been studying and looking for a vaccine to counteract the effects of this new type of coronavirus (Lin et al., 2003, 2020).
Its symptomatology has been studied and it has been seen how it affects people who suffer from it. The most serious symptoms that have been diagnosed are a fragilisation of the lung tissue into an inelastic tissue with a feeling of shortness of breath or air, chest pain or pressure, and an inability to speak or move. Other less common symptoms that have been detected include: dry cough, small tumours in the upper and lower extremities, fatigue, sore throat, diarrhoea, conjunctivitis, loss of sense of smell or taste, headache, diabetes, skin rashes, or loss of colour in the fingers and toes (Cheng et al., 2020; Corman et al., 2018; Dahirel et al., 2011; Fu et al., 2020; Huang et al., 2020; VijayKrishna, 2007; WHO, 2005a, 2005b)
In the face of this pandemic, the scientific community is acting in a coordinated manner and with sufficient resources to find a vaccine as soon as possible. More than a hundred projects are currently being developed, some of which are already at an advanced stage.
The Vaccine and its Importance
For the moment, until a vaccine is found, SARS-CoV-2 coronavirus will be able to circulate freely among people, who will be fully exposed to the pathogen. This new virus has shown a higher capacity of contagion than originally estimated, which has allowed it to spread throughout the world very quickly, as indicated by the figures of contagion and deaths in scientific studies being conducted since its inception in Wuhan (China) (Hoehl et al., 2020; Kanne & Chest, 2020; Li et al., 2020; Sanglier et al., 2020c; Wang et al., 2020).
Vaccines are biological preparations, which after being administered, are capable of producing an immune response, specific, effective and artificial against microorganisms, that is, a preparation whose function is to generate the body’s immunity against a certain disease, stimulating it to produce antibodies that will then act to protect it against future infections, since the immune system will be able to recognise the infectious agent and destroy it.
Vaccines are divided into monovalent (they have only one antigen), polyvalent (several antigens of the same species, meningococcus) and combined (several antigens of different species, diphtheria, tetanus).
Currently, there are combined vaccines, such as trivalent or hexavalent, which allow simultaneous immunization against several important diseases. And all this without appreciable risks, since the adverse effects of vaccines are very mild (mild redness and pain at the injection site, fever or muscle aches) and very rarely serious. The vaccines are administered intramuscularly and in some cases orally. Several time-spaced doses are usually necessary to achieve sustained immunity over time (Ramaiah & Arumugaswani, 2020; Vita et al., 2019).
Any hygienic measures taken, such as the use of masks or physical distancing, will continue to be very effective and may slow the rate of infection to relatively safe levels, but a return to the pre-pandemic situation will depend on finding therapeutic solutions. Among these, the vaccine is the most important.
Is It Just a Vaccine or Something Else?
A fierce race has begun towards the development of that vaccine to end this pandemic, but there are many other things at stake at the level of scientific development and economic interests in selling the final product. However, there are different challenges that make this challenge, due to the different circumstances that surround it, one of the most important that science has faced in its history: Shorten manufacturing times, which in all vaccine developments are usually long because of the different phases it has to go through. The final vaccine, in addition to being effective, must be able to be manufactured on a large scale, in order to spread it globally. Ensure vaccination campaigns, which in this case, must be massive.
Some experts, the less optimistic ones, say that the efforts made by scientists in search of the vaccine could be in vain but considering that most of the patients who have passed the virus have responded immunologically, there seems to be a glimmer of hope in the achievement of the COVID-19 vaccine.
Time Required
Scientists have projected a time frame of 12–18 months to find a viable and effective vaccine (Chakraborty & Barton, 2017; Liu et al., 2020). In general, the processes have been accelerated to a maximum, however, there are stages in the methodology that cannot be shortened and that need months to be tested. It is evident that for people, for humanity, time seems eternal, it seems that it will be played with the relativity of time and Einstein’s theories. The doomsayers show that the times to find the solution could be years and even decades, I do not know if you could expect so much having such a fierce and threatening pandemic out there.
The development of effective vaccines generally shows a high error rate. Scientists use processes that are usually linear, and avoid making false steps, before moving on to the next phase. Nowadays, this has been changed, and it depends on the urgency, in this case, a lot, the processes are carried out in parallel to go faster and tend to abandon the previous linear scheme. The aim is to shorten the time to reach the solution sooner, even if this increases the risk of failure. One of the actions or measures taken is to start the clinical phase in humans before the end of the phase in animal models (Lan et al., 2020; Liu & Wang, 2020). The vaccine is also beginning to be mass-marketed, even before it is known whether it will be successful or not. As we can see, the behaviour of scientists has changed and everything has accelerated in order to achieve a solution as soon as possible, nothing more or less than the future of humanity is at stake (Lu et al., 2020).
Phases of a Vaccine
The development of a vaccine can be done in the following phases:
Phase 0: Also called pre-clinical, this phase includes in vitro and animal testing. The vaccine must be shown to be safe and to work in animal organisms. If you respond adequately, you move on to the clinical trial which is usually divided into three sub-phases plus an optional fourth. Sub-phase 1: The vaccine is tested on samples of a small human population, in groups of 20–100 healthy people. This is done to demonstrate that the vaccine can be safely applied in the human population and to be able to see and analyse possible side effects, if any. The right amount of vaccine doses is also studied. Sub-phase 2: In this phase, the sample of the population to be studied is increased, and already applies to a population of several hundred people. The most common possible short-term side effects and how people’s immune systems react are reassessed. Sub-phase 3: The population of people to be educated continues to increase and extends to thousands of people. In this sub-phase, the evolution of vaccinated persons is compared with those who were not vaccinated. In addition, statistical data are collected on the effectiveness of the vaccine and its safety. Possible new side effects are checked in people who were not detected in the previous sub-phase. Sub-phase 4: It is a voluntary confirmation phase where the vaccine is further tested after being approved for manufacture and production. The main goal is to get more information about the vaccine so that it becomes more effective and safe.
Vaccine Projects
On 9 June, the World Health Organization (WHO) recognised 126 projects that have found a vaccine candidate and are in phase 0 or pre-clinical since the coronavirus outbreak was declared an epidemic. There are 10 other projects that have passed this phase and are already in the clinical phase with human testing.
The following are the most advanced projects in search of the definitive vaccine: CanSino Biological Inc./Beijing Institute of Biotechnology (China): This project is already in sub-phase 2, where a viral vector vaccine is being developed. It is a subunit vaccine (new generation formula that does not contain pathogens), and very safe. Tests have been conducted on people with satisfactory results. The population sample has now been expanded to test for efficacy, safety and possible side effects ( Modern/National Institute of Infectious Diseases NIAID (USA): This project is in sub-phase 2. A viral vector vaccine, combined with the genetic code of the virus, is performed. It is being developed at a productive level by means of a pharmaceutical, and the first tests on humans have given positive results. They will continue with the trials ( Sinophram/Wuhan Institute of Biological Products and Sinopharm/Beijing Institute of Products (China): This vaccine developed by the union of these two Institutes is in sub-phases 1 and 2. Two very promising independent projects have been developed, based on inactive viruses. Launched by Sinopharm, the state-owned pharmaceutical giant. ( Sinovac (China): It is found in sub-phases 1 and 2. It works with a purified inactive virus and has generated many expectations after scientifically demonstrating that this vaccine is capable of generating effective antibodies against coronavirus in macaques, rats and mice. Human testing is scheduled to begin later this year ( Jenner Institute, Oxford University, UK: This vaccine is in sub-phases 1 and 2. ( BioNTech/Pfizer (Germany/USA): This vaccine is in sub-phases 1 and 2. BioNTech, allied with the American pharmaceutical company Pfizer in January of this year to obtain an effective and safe vaccine. It has been successfully tested in mice and is already being tested in humans with four variants of a synthetic messenger RNA-based candidate. The multiple approaches of this project allow a simultaneous assessment to be made to increase the chances of identifying the safest and most effective potential candidate. ( Inovio Pharmaceutical (USA): This project is in sub-phase 1. This vaccine candidate will be tested in humans in April based on the virus’ RNA ( Novavax (USA): This project is in sub-phase 1. He has just started human clinical trials with his protein subunit-based candidate, and expects to have the first results by July, where, depending on the results obtained, the second sub-phase would begin ( Institute of Medical Biology (China): The project is in sub-phase 1. It is another of the Chinese vaccine candidate projects. He just started his human trials. It is a project based on the inactive virus (
In Spain, research is also being carried out on a vaccine that can tackle the coronavirus. To date, there are 10 projects that make a difference, but for now, they are in the preclinical or phase 0 phase. The most outstanding projects are:
The National Centre for Biotechnology, which belongs to the Spanish National Research Council (CSIC) (
There is another team at the same centre that is working on creating a vaccine from a genetic reconstruction of the coronavirus itself, attenuating and eliminating the most virulent genes, with the possibility of soon having a viable vaccine candidate.
And there is a third group of CSIC researchers who are looking for a vaccine using a coronavirus antigen to stimulate immunity. The method consists of placing the antigen gene in the synthetic ‘vehicle’ of genetic material that can be introduced into the patient’s body and induce protection against infection. It is believed that in two months it will be tested on mice.
Other Solutions
In addition to vaccines, there is another line of research to combat the coronavirus, and that line is drugs (Ahmed et al., 2019; Deming et al., 2006). According to estimates, some 200 new investigational drugs, mostly antiviral, have been identified that could combat the new coronavirus.
The use of existing drugs to combat the new coronavirus has multiplied in the last weeks of the pandemic. Around 1,700 clinical trials have been registered, of which approximately 80 are being carried out in Spain.
These existing or developing drugs, administered individually or in combination, are mainly divided into three groups (Ferguson et al., 2013; Graham et al., 2012; Ramaiah & Arumugaswami, 2020; Yang et al., 2004): Those intended to prevent the virus from progressing within the human body. Those designed to calm the immune system’s response (in the most severe cases of the disease, an exaggerated and potentially fatal immune reaction is triggered, called a ‘cytokine storm’). Those based on antibodies, either obtained in laboratories or from the blood plasma of patients who have overcome the disease.
Since the beginning of the pandemic, the treatments used have been oriented towards three objectives: antiviral, anti-inflammatory and antibiotic (viral infections are often associated with bacterial infections). However, clinical evidence has led to the addition of other drugs such as antithrombotics or anticoagulants over the weeks (Fan et al., 2009; Letko & Munster, 2020; Pickett et al., 2012; Prabakaran et al., 2006; Quadeer et al., 2018; Zhu et al., 2020).
Conclusion
As can be deduced from the above study, the leading research centres in Virology, Pathogens and the study of rare diseases are fighting to find as soon as possible a vaccine that can, for the time being, bring humanity to safety. At the moment, hopes are pinned on five Chinese research centres, four American, one British and one German, as the leading or most advanced centres in terms of clinical sub-phases applied to arrive at an effective and safe vaccine definitively.
From what has been analysed so far, the most advanced centres are in sub-phase 2 and are a Chinese centre (Institute of Biotechnology) and an American one (Modern/National Institute of Infectious Diseases (NIAID)). There are five other centres between sub-phases 1 and 2, and the remaining centres (three) at the forefront of research to achieve the final vaccine are in sub-phase 1.
Apart from vaccines, which will still take some time, drugs are another possible short-term solution. There are some drugs where their safety has already been proven, among them are Remdesivir (Ebola), the only one already in clinical phase 3, prior to commercialization; Lopinavir and Ritonavir, Hydroxychloroquine and Chloroquine (malaria). However, according to clinical data, the latter two drugs do not appear to provide any benefit over patients treated with COVID-19. In view of the doubts generated, the WHO has decided to suspend all its hydroxychloroquine trials while the risks are reviewed.
There are other drugs whose development is based on antibodies and where several researches worldwide focus their efforts on identifying proteins that prevent the SARS-CoV-2 virus from parasitising human cells and using them to replicate its genetic material. Two independent laboratories, one in the Netherlands and one in Israel, have already obtained antibodies capable of neutralising it, following the example of other diseases already treated with this same technique.
One of the measures to see the number of people infected by the virus, has been the vaccination of a part of the population to which are added the people who are immune because they have developed antibodies after a previous infection, this is called ‘herd or collective immunity’, which provides indirect protection to the non-vaccinated individuals.
Epidemiologists estimate that 60%–70% of the population needs to be immune to the virus to achieve this kind of collective immunity.
Until the vaccine arrives, there are very conflicting positions on taking action. There are advocates that contagion should occur freely without putting in place any measures to combat it, with the intention of increasing herd immunity in the population. This allows an increase in the number of positive cases and in the number of people circulating to increase the generation of antibodies and the creation of an immune barrier. But this strategy does not seem to be a good solution, as it could lead the health system to a situation of collapse, and consequently, to the death of a large number of patients.
In Spain, the first data from the seroprevalence study carried out by the Ministry of Health are quite discouraging in this regard. Only 5% of the Spanish population would have generated antibodies, so this ‘herd immunity’ without a vaccine seems an extremely difficult horizon to reach, especially considering the high human, health and economic costs that such a low percentage has implied.
Who will reach the goal first, is a dilemma that we hope will soon have a solution, the important thing is to reach that goal that for now seems a little distant.
Discussion
The fact that only 5% of Spaniards have been in contact with the most destructive pathogen of this century leaves citizens at the mercy of the discovery of a vaccine: the only thing that could guarantee the famous herd immunity, and that most people could return to normal life without the risk of infection. In this race against the clock in which there is no limit to the number of participants, there are several major obstacles. Overcoming them will be necessary so that the desired immunization can be given to healthy people.
Now vaccines cannot or should not be developed that would be counterproductive for the population, as was the case in 1996 in the United States, where the first vaccine against the respiratory syncytial virus was tested, because controls are very demanding. This is something that slows down the process, but it is necessary. A vaccine is not given to repair the damage, but to prevent it. This means that the sample sizes for testing have to be much larger than those used in the drugs.
There are four main vaccine routes to combat the new coronavirus, one using attenuated virus, one using recombinant DNA, one using RNA and one based on recombinant purified antigens. The new vaccines are never easy to obtain, it is a very complex biological product, and the research capacity is what it is.
Although the results could be encouraging, there are groups of scientists who have reached sub-phase 2, many more experiments have to be performed, to analyse how the immune system is stimulated, to see the correlation between the different parameters of protection against the virus (protective correlates). Antibodies and cellular immunity have to be studied. Currently, there is very interesting work regarding the cellular immunity that induces SARS-COv-2 infection and that is very relevant when designing vaccine candidates.
We also have the problem of the circulation of the virus, it could be that it circulates little or not at all when it comes to demonstrating its effectiveness on a large scale. One possible solution, this has been suggested before, would be to purposefully infect volunteers in a controlled way, this is a very controversial open debate especially for a disease for which there is no treatment, with very serious complications even with death of the patients, and there are many ethical aspects to consider.
A bet could be made to start vaccination in high-prevalence areas and see if vaccinated individuals do not get infected or get infected only very mildly. This type of procedure is usually followed to test vaccines such as tuberculosis. It is initially studied in volunteers to assess toxicity, but the successive clinical phases are done in countries with high incidence. Groups that are vaccinated are then compared with groups that are not, and the percentage of people infected in each group is analysed.
Assuming that the first part of development is overcome and a prototype of the COVID-19 vaccine will soon be available, we are now entering the production part. You’d have the brake on mass production. Despite advances in pharmaceutical R&D, the technology has been around for many years and has not evolved much. The time it takes to develop the product, once you have it, and to manufacture it remains the same. It is estimated, objectively, that the time to achieve a large-scale vaccine with millions of doses will be between 14 and 18 months from the start of the research. This ‘long time’ could be solved with alliances and business clusters that could use multi-dose vials among other solutions. The antigen should be produced in GMP (good manufacturing practice) companies, but this, in turn, could trigger a ‘bottleneck’.
Recently, outbreaks of the new coronavirus have begun to be detected, suggesting that the factor of speed in the manufacture of the vaccine is becoming increasingly important. You can choose to start making it before you know if it is effective as researchers at Oxford University have done in human clinical trials.
The pharmaceutical industry seems to have committed itself to produce it on a large scale while it is in sub-phases 1 and 2 of development. However, a pharmaceutical product can only be legally manufactured when it reaches sub-phase 3, which includes a clinical trial in humans. Ideally, the technology should generate faster product development, which is scalable and cost-efficient. The future points to recombinant proteins, which are the drugs of the future, however, the technologies applied to produce them are always based on bioreactors, which are very complex and expensive facilities.
We enter a phase where we have to weigh up the speed in order to get the required information as soon as possible to first select from the vaccines that are being developed which one of them can be more or less effective, without ignoring the safety of the vaccine. In a rush, there is always a possible decrease in vaccine safety. In this case, the risk/benefit of protection must be assessed. At this moment, the processes are being speeded up in a very important way, especially skipping the study in animal models and going directly to test in humans.
Even if the steps in the development and production of the antigen are shortened, there are other difficulties to be taken into account. There might be a logical temptation for the country that finds the vaccine first to want to vaccinate its population first, but to avoid this are the institutions. One could consider giving priority to the administration of the vaccine, in the country where the virus is circulating at that time. It is estimated that about 7 billion doses would be needed immediately; assuming that one dose would be sufficient and that other types of vaccines would be discontinued. WHO is expected to be the agency that provides order and sanity in the delivery and distribution of vaccines.
To provide the vaccine at the same time and to everyone seems an impossible task, so priority should be given to the most vulnerable population, to the health workers and the elderly, perhaps also to the state security forces. But it would depend on the characteristics of the vaccine, because it might work, for example, better in the young population.
The economic issue also plays an important role, some politicians are betting on a shared risk, that is, that the governments contribute economically to the development and production of the vaccines, risking to be betting on a product that finally does not work. It must be taken into account that the development of a vaccine from its initial phases is very costly in terms of time for experimentation, and in its implementation, passing through the different clinical phases required for final approval by the regulatory agencies, in addition to the added cost of producing the vaccine.
The cost of the vaccine will depend on the type of vaccine you have. If the pathogen is attenuated, for example, it has to be grown under GMP conditions, it may not grow well, it may have to be repeated. You have to look for cells that can be infected by a particular virus, and not many companies can manufacture this type of vaccine. It must be taken into account that the safety and regulation conditions are very extreme to work with pathogens. It can also happen that the successful vaccine is developed with protein, DNA, and RNA components. In that case, the type of production is different, of course also under GMP conditions, but in a different way, and it is usually other types of biotechnology companies that could develop them. It is also necessary to see what kind of adjuvants are used, and what kind of combination is finally used. These are certain conditions that must be taken into account, he specifies.
All these reflections lead to the conclusion that the important thing, in the end, will be to reach the goal and get the right vaccine so that humanity, this time, will be safe. What will happen next? We do not know, but what seems to be true is that this time the work has been done side by side, that the work has been done differently and that the efforts of many scientists from all over the world have been united, sharing more than other times, to achieve the common goal, to find the COVID-19 vaccine.
Footnotes
Acknowledgements
The author would like to thank the Universidad CEU – San Pablo, and especially the Escuela Politécnica Superior of Madrid (Spain).
Declaration of Conflicting Interests
Funding
The author received no financial support for the research, authorship and/or publication of this article.
