In the face of the current situation, which will undoubtedly mark humanity forever, a race against time has been generated to try to overcome it as quickly as possible. Not in vain, in less than a year it has shown us how vulnerable we are, but also our resilience. The most promising weapons with which we will fight will be vaccines. However, doubts, suspicions, and misgivings are weighing on many people. People haven’t been too happy about that the time for developing vaccines, which has usually been between 10 and 15 years, has been reduced to a few months. Does this mean that they are unsafe? Will they put our lives at risk? Do they respond to an obscure plan of the global elites? We will try to answer these questions in this second part
The characteristics of the ideal vaccine
Surely it is clear to everyone that vaccines have to go through an extremely strict control and regulation process. Indeed, vaccines, like drugs, have to meet a large number of requirements to be considered suitable. These conditions mainly refer to the safety and effectiveness of the product.
First of all, the vaccine that comes to the market must be completely safe. Safety is understood as not causing a worse diagnosis than that of the disease it is trying to prevent, nor triggering the pathology (for example, an attenuated vaccine can be dangerous for an immunocompromised person). Vaccines can generate side effects, but only if they are transitory and do not jeopardize the integrity and quality of life of the patient. These effects can occur locally (pain at the injection site, swelling, redness, inflammation) or systemically (fever, fatigue, flu-like symptoms) and are usually triggered by inflammatory processes.
On the other hand, the vaccine has to work, that is, it has to be effective enough to ensure efficient and long-lasting immune protection in most patients. Therefore, not only does it have to train the immune system to prevent the disease from developing and the pathogen from lodging in the organism in future encounters (the good vaccine avoids both the symptoms and the contagion), it must also establish that line of defense as long as possible through a strong immune memory. What is that effectiveness based on? The effective vaccine, that is, the one with a potent immunogenicity, must be capable of stimulating the secretion of neutralizing antibodies and of B and T cells. Although normally we only speak of the antibodies in the context of the immune protection, lymphocytes are also fundamental, and especially against strict intracellular pathogens such as viruses. In the first part we explain how all these elements act against a viral infection and how the immune memory is generated:
The SARS-CoV-2 vaccines. Part 1: The mechanisms of vaccines
In addition, there are a number of practical issues that unfortunately cannot always be achieved, but are desirable to encourage and facilitate the distribution, application, and effectiveness of vaccines. For example, many times the vaccine itself does not have the required immunogenicity, so, in order to strengthen it, adjuvants are needed, which we also talked about in the first part.
It is always better for the vaccine to work with a single dose than with several boosters. In this way, it is easier to follow up the vaccinated population, it is less laborious to apply (especially for isolated and dispersed communities), it accelerates the achievement of collective immunity, it reduces production problems, it can be accessed earlier and its price is reduced. Nevertheless, the number of doses needed to ensure an adequate protection already depends on the vaccine. Some, such as Hepatitis A vaccine, ensure such protection for more than 20 years with a single dose. However, tetanus requires a booster every 10 years.
The economic cost of a vaccine is an important factor determining its affordability. It depends on many issues. One of them is the complexity of the storage required by the vaccine (which, in turn, is related to the biological stability of the antigens that constitute the base of the vaccines: nucleic acids, proteins, the pathogen itself). The more sophisticated and complex it is (for example, if it needs to be stored in an ultra-cold chain of -60 ºC), the more expensive it will be. Of course, it should be added that many countries do not even have the infrastructure or technology to be able to store vaccines in such conditions. Likewise, the complexity of the vaccine manufacturing process also increases costs.
When we think of a vaccine, we tend to recreate its administration by means of a painful intramuscular injection, but the truth is that there is a great diversity of ways to inoculate a vaccine, some more practical than others. The classic form, the injected one, is impractical and, in addition, expensive, since many materials and qualified personnel are needed to apply it. It is also an invasive technique, certainly painful, and laborious when applied massively. And this may seem a truism, but it is also important: the injection recreates an infection route rarely used by pathogens. Most of them usually invade the body through the nasopharyngeal mucous membranes. Wouldn’t it be better to ensure the protection of that area first? This seems obvious and easy, but it is not. In fact, the injection, although impractical, ensures the integrity of the antigens that constitute the vaccine. If it were administered orally, for example, it is very likely that the digestive enzymes would destroy the antigens and the vaccine would not have any effect. On the other hand, the immune system of the digestive tract is adapted to develop tolerance to the antigens entering it instead of an offensive reaction. It makes sense, otherwise the nutrients would be considered elements to be destroyed. Be that as it may, scientists have been working for a long time on oral or nasal vaccines to stimulate the defenses of those body regions as soon as possible. Regarding COVID-19 vaccines, there are a few candidates who, if approved, would follow these inoculation routes.
All these conditions are taken into account when approving a vaccine. However, to be successful once it has been approved, it is essential to have the support and trust of the population and experts. Unfortunately, deception, hoaxes, and conspiracy theories can undermine the positive perception of the population and drive the success of the diseases.
Recall, for example, the rise of measles in the United Kingdom, the United States, and other countries following the 1998 publication in The Lancet by former Dr. Andrew Wakefield and colleagues that fraudulently associated the MMR vaccine (triple vaccine against measles, mumps, and rubella) with an increased risk of autism and chronic intestinal disease in children. This study was a blast that spread around the world. The consequences? It fed the denial and suspicion of thousands of people, who stopped getting vaccinated. The anti-vaccine movement found the ideal niche from which to spread its lies (in fact, that study, which was removed long ago from The Lancet and refuted by dozens of scientists, continues to be one of the movement’s favorite fallacies). The population was the victim of a great hoax and paid dearly for it. There were many deaths and fatal diagnoses associated with measles.
Years later, Wakefield’s conflicts of interest would be discovered, which he deliberately concealed, and for which his collaborators withdrew their support and retracted the conclusions of the study. Wakefield blatantly insulted the scientific code of ethics, not only because of the lies and manipulations, but also because he employed children in his trials without receiving any approval from ethics committees. It seems that he had devised a ruse: to found a company with which, taking advantage of the growing mistrust of the vaccines he was feeding, he would profit by conducting medical examinations of children vaccinated with the MMR vaccine and advising in litigation the alleged victims of the vaccines. Unfortunately, until 2010, when a court revoked his license to continue practicing medicine, The Lancet would not withdraw the article for fraud. Since then, this guy has continued to do the only thing he is good at: profiting from deception and cajolery through the anti-vaccine movement, of which he has been a spokesperson for several years. Measles, a pathology considered eradicated in many countries, continues to experience various outbreaks around the world thanks to the fear fed by the anti-vaccine movement. Without going too far back in time, in 2019 the WHO warned of the appearance of 90,000 cases of measles in Europe.
The testing phases of vaccines. Why have they been so summarized?
All of the above conditions apply to all vaccines, including the SARS-CoV-2 vaccine. As we can see, there are many criteria that vaccines must meet, which explains why, of all the possible candidates, very few manage to achieve the final goal. All of these criteria are evaluated in a series of steps or phases that are extremely regulated and full of tests that candidate vaccines must pass. And this is where the great controversy surrounding SARS-CoV-2 vaccines lies. As we will see, this process takes on average 10-15 years. Almost three lustrums are dedicated to testing the safety and efficacy of the vaccine so that the final product is as good as possible.
In the extraordinary and very serious pandemic in which we are immersed, scientists have greatly shortened that time, and that is the basis for the suspicions of those most reluctant to get any of the vaccines that are about to come out or are already being distributed. Why has that happened? Have they cheated, as some people think, and skipped phases to get the vaccines out as soon as possible under political and economic pressure? The point is that this time summary has its rationale. We will understand it better later. At the moment, it seems that everyone knows that any vaccine takes a very long time to reach the final goal. Why? Let’s study these phases in detail to understand them.
Let’s start by saying that a vaccine has to go through two major phases. In the first one, as it is logical, all the efforts are focused on knowing in depth the pathogen in question: its infection and propagation routes, its virulence, its action mechanisms, its mutation rate, its biochemical structure, the type of immune response it triggers in the host, its antigens, its genome… In the first phase, therefore, scientists elaborate the pathogen’s biography. This information is essential, because it will determine what will be used as a vaccine, i.e. the antigen: the whole pathogen attenuated or inactivated, some of its purified proteins, the pathogen recombinated, some specific gene or genes, its nucleic acid… Only this documentary exercise usually takes 2 to 4 years under normal conditions.
Once the antigen that is going to constitute the base of the vaccine has been selected, it’s time to evaluate its biochemical characteristics, its effectiveness or immunogenic potency, the vector in which it will be included if it is needed, the adjuvants that will accompany it if they are necessary, the safest and most effective dose, harmful effects, etc. To test the antigen, it is necessary to have the doses in which it will be included. Consequently, it is necessary to build or recondition factories with the adequate equipment to manufacture thousands of doses of the test vaccine.
The safety and efficacy of the candidate vaccine are examined in two broad phases: the preclinical phase and the clinical phase, in which voluntary people are used as test subjects. In the preclinical phase, one or two types of trials are conducted:
In vitro trials, for which human or animal cell cultures and purified antibodies are used. Sophisticated computer models can also be used.
In vivo trials with animals. These are much more complex systems and reproduce with greater accuracy the human organism for which the vaccine is intended. However, they present several problems. The use of laboratory animals is expensive and complex at a bureaucratic level. It is obligatory that an independent ethics committee approves the trials, for which it must be demonstrated that the suffering of the subjects will be reduced as much as possible and that the trials are justified. Likewise, the factors that influence the results obtained are extremely diverse. On the one hand, it is necessary to bear in mind the variability between individuals, which can generate different results that make interpretation difficult. The fact that each individual is a world is totally true. On the other hand, environmental conditions and the state of health and stress of animals also influence the results.
The pre-clinical phase is used to obtain very preliminary results on the vaccine. We must bear in mind that in vitro or in vivo systems with animals are far from reproducing the “human system”. The results guide us on the behavior of the vaccine, but the extrapolations from them are not realistic to obtain an adaptable interpretation of its effects on people. Therefore, it is necessary to continue testing the vaccine in people in a controlled laboratory environment. Thus, we gradually obtain an increasingly precise and realistic understanding of the vaccine. Preclinical trials can take more than one year.
When the antigen studied is sufficiently immunogenic and safe in vitro and/or in vivo, it is time to start the clinical phase with people. In 4 consecutive phases that can last up to 6 or 8 years, the vaccine is tested on an increasing number of people to evaluate its safety and efficacy. And since we talk so many times about efficacy, let’s make a brief parenthesis to explain a semantic issue. Even though they are often used indifferently, the efficacy and the effectiveness of a vaccine are not the same thing. The efficacy refers to the degree of protection of a vaccine in optimal and controlled laboratory conditions, that is to say, those that are reproduced during the clinical period, and it is a preliminary value that serves to achieve the approval of the competent agencies. On the other hand, the effectiveness is obtained in real conditions, when the vaccine, once approved, is already massively used in the population. This is the value that objectively defines the true potency of a vaccine.
In the clinical phases, the normal procedure is to proceed through double-blind randomized trials, that is, a randomized group of participants is given the vaccine and another (the control group) is given a placebo or a reference drug, normally in a ratio of 1:1. Until the end of the trials, neither patients nor experimenters know which group each person belongs to (double-blind). In this way, observer bias and the placebo effect, which can alter the exegesis of the results, are avoided. Without further ado, let’s see what the clinical phases are:
In the first phase of the clinical trials, a few dozen people are selected with one requirement: they must be healthy. The main objective is to test the toxicity of the vaccine. In this phase, short-term adverse effects begin to be scrutinized. Average duration: 1.6 years.
In the second phase, the population sample is increased to several hundreds of people. With a greater number of cases, more concise results are obtained and allow confirming or not those obtained in the previous phase. Side effects continue to be monitored and the type of immune response that triggers the candidate vaccine begins to be studied. At this time, other variables are introduced into the equation that may influence the results, such as sex, the patient’s immune status, or age. Likewise, the safest and most immunogenic doses of the vaccine and the administration pattern are established. Average duration: 2.9 years.
Age is a factor that has an enormous influence on the efficacy of vaccines. The immune system of a child, a young adult, and an elderly person are different, function differently, and have different states of “health” and development. Apart from immune pathologies, the immune system of the child is still in formation, that of the adult is fully formed and that of the elderly is aged. In the latter case, the reserves of memory lymphocytes are relatively impoverished. With the passing of the years, these reserves are exhausted; unfortunately, they are not unlimited. Therefore, the secondary response to the reappearance of the pathogen is more deficient in older people. In fact, in the elderly, as in children, the predominant is the innate immune system: in children because the adaptive immune system is formed and trained with exposure to pathogens throughout life and in the elderly because it is aged. Logically, the efficacy of vaccines varies depending on the age of the people. In fact, it is known that, for example, flu vaccines are often less effective in the elderly than in adults or young people. This is why it is important that different types of vaccines are released, because some will be more effective in certain age groups than others, thus ensuring the protection of the entire population.
In the third phase of the clinical trial, the sample size is again increased, this time by tens of thousands of people. In this stage, the intention is to compare the clinical evolution of the vaccinated participants with the control group. The estimated efficacy is already more precise and realistic. It is very easy to calculate. Let’s imagine that we have 19548 people who have received the vaccine and 19792 who have received the placebo (control group). In the vaccinated group 15 people have been detected to have fallen ill after receiving the vaccine and in the control group 218. From here we can calculate a value known as relative risk, which is the probability of occurence of an event, in this case, the disease. It is very easy to obtain. Following our example, it would be as follows (15/19548) / (218/19792) = 0.07. Finally, the efficacy is calculated as follows: 1 – 0.07 = 0.93, which expressed as a percentage would be 93%. That would be the efficacy of our imaginary vaccine. Average duration: 3.8 years.
Once the third phase has been completed, it is essential to generate a final report with all the information gathered until then and with proposals on which facilities can be used to manufacture the vaccine at an industrial level and the manufacturing methodology. This document will have to be submitted to the corresponding drug regulatory agencies in each region (in Europe, the European Medicines Agency; in the United States, the Food and Drug Administration or FDA, etc.), who, after carefully analyzing all the information, will authorize its commercialization if they see it convenient. In the case of COVID-19 vaccines, the FDA requires that they have at least 50% efficay to be approved. The approval process can take up to 18 months in normal conditions. This step is critical and very strict. If experts believe the vaccine is effective in preventing the disease and it is approved, we can be confident that it is. Most experts agree that the SARS-CoV-2 vaccines will not be approved by the appropriate agencies just because, but since they will be effective and safe.
The trials do not end once vaccines are approved. Then, the production of the vaccine on an industrial scale begins, including the purification and isolation of the antigen on which it is based. Once the vaccine is being applied on a large scale, it is when the fourth and last clinical phase begins. The safety and efficacy of the vaccine continue to be examined (and now also the effectiveness) with the objective of knowing if it has to be modified to improve its characteristics, if there is any severe negative reaction that may appear in the long term, if there are adverse reactions that appear more frequently in some population groups than in others…
One of the main fears of some people is the possible unstudied side effects. Well, let it be clear that the usual thing is to launch a vaccine without knowing absolutely all the possible adverse reactions it may cause (especially the atypical ones). Anyway, at this point there would be little to worry about, since severe adverse reactions usually appear 6 weeks or two months after the vaccination (and the same applies to COVID-19 vaccines).
Why do vaccine trials take so long? Much of the blame lies with bureaucracy and quality controls. Every time a trial is finished, the authors must generate a dossier with the protocols they have followed, the results obtained, their interpretation, the fulfillment of all the technical and ethical requirements, etc. These reports will then be analysed by various expert committees, that will authorise whether or not to jump to the next phase. As the trials progress, the controls are becoming much stricter. The requirements are more rigorous and if they are not achieved, the trials stop. And, of course, the corresponding peer-reviewed scientific articles must also be generated and published in competent journals so that the rest of the scientific community can review this information.
As we see, it takes a lot of time to produce a safe and effective vaccine. Seventy percent of that time is consumed by quality controls, the generation of reports, and the review by competent committees, procedures that are omnipresent throughout the study and development process to certify the criteria that a vaccine must meet. In other words, the manufacture of a vaccine is a highly guaranteed process and it is very difficult for a defective product to reach the market. During this process it is also essential to ensure transparency in the data to generate security in the population and in the scientific community, something that not all countries practice with the same effort (something that, unfortunately, has been violated a few times in relation to COVID-19 vaccines).
In this context, natural selection also works: only a few of all candidate vaccines are finally released due to the strict controls they must pass. It is estimated that 33.8% of the vaccines that reach phase 1 of the clinical stage end up being approved by the authorities, quite a lot if we compare them with drugs, of which only 13.8% manage to be approved.
Now comes the key question: Why has the testing time been reduced so much with the coronavirus vaccines? Are the phases being skipped? We are in an extraordinary and critical situation, which requires action against time and an extreme synthesis of the trial phases. The incredible effort of hundreds of scientists from all over the world and the information already available helps to explain in part this time saving. First of all, a lot of work and funds have been dedicated to learn about SARS-CoV-2 (estimated at about 7 billion dollars) and the antigens with the greatest potential for developing the vaccine, with the spike surface protein being the undisputed protagonist. Add to this all that was already known about the relatives of the new coronavirus, SARS-CoV-1 and MERS. Although there are many differences between them, there is also a high percentage of similarities that can be applied to SARS-CoV-2. This would explain why in a few months we have obtained the basic information about the virus to start working on vaccines.
In the process of developing vaccines, testing phases are sequential, and until one is finished and the expert committees give the green light, the next one does not begin. However, in order to accelerate the development of the vaccines against COVID-19, the different phases have been executed in parallel, but they are not skipping, as some have even suggested. In the articles that are being published progressively this fact can be verified: how some have merged clinical phase 1 with phase 2 or phase 2 with phase 3, etc. Another example: some research teams have started the preclinical and clinical phases almost at the same time. Furthermore, in some cases the preclinical phase is being carried out on several species of animals at the same time, when the normal thing is that, after testing it on one species, it is started on another. On the other hand, at the same time that vaccines are being evaluated, the specific factories and machinery are being built and the stock of vaccines that will be distributed throughout the world once they are approved is being manufactured, a step that is carried out when the clinical phases have reached their end in normal conditions. These actions entail a very risky investment for the future, because no one can be sure that the vaccines will be successful. Even so, in the face of this serious situation, these are risks that must be taken.
As we said, the assessment of results and their approval takes 70% of the time. Well, this has also been significantly synthesized. For example, in the European Union, the European Medicines Agency is following the rolling review method for the evaluation of results. Instead of waiting for all the results to be compiled for their analysis, they are analyzed as they come out to save time.
If any research try to skip any of the testing phases, that vaccine would have no future. It is unlikely that the vaccines that finally reach the market will constitute a serious risk to the population. In fact, treatments are at greater risk than people. Let me explain. Speeding up the research process for a vaccine increases the probability of making mistakes or missing something. Thus, the experimental treatment is more likely to fail and not being able to continue to the next phases. In any case, one thing should be clear: even though the time for developing the vaccines has been reduced, the COVID-19 vaccines have to go through multiple barriers and filters made up by the scientific committees, the same ones any other vaccine has gone through. Therefore, the vaccine that overcomes all these barriers and is authorized will not be precisely by chance. It will be a safe and effective vaccine. Logically, there will be some additional risks than if the vaccine had been studied for a longer time. As we will see below, certain population groups have not been taken into account in many of the investigations, such as pregnant women, people with allergies…, and it is not yet known how the treatment will evolve in them.
After reading this, many people will still be reluctant to get a vaccine. Why in other cases it takes even several decades to obtain an effective vaccine, as with HIV, which will take half a century in total, or chickenpox, which took 28 years? The time it takes to develop a vaccine also depends greatly on the characteristics of the pathogen. HIV is a virus with a very high mutation rate, it changes frequently, to the point that a sick person may have several different strains of HIV in her body. The same happens with the flu: almost every year is necessary to develop a new vaccine to combat it, because it changes and each new strain can invalidate the vaccines of previous years. However, we are fortunate that SARS-CoV-2 mutates relatively little. Nevertheless, even though its mutation rate is low, it is only a matter of time before it changes enough to render the vaccines in development useless.
We tend to see only the negative side of things. We also tend to exaggerate a lot. But why don’t we reason in the opposite direction? What if this pandemic is giving us a lesson in what human beings are capable of? What if the speed with which vaccines are being developed (some of them totally novel, such as messenger RNA) is a turning point that will lead to a modification of the protocols for studying and producing vaccines in order to make them faster while maintaining their effectiveness and safety? Perhaps we will discover that we can develop vaccines much faster than we thought and with more than acceptable effectiveness. Perhaps we are at the next milestone in preventive medicine, which would mean tackling more quickly emerging diseases and others that we have been dealing with for decades.
Features and properties of the most famous vaccines
Are the COVID-19 vaccines that are going to be released safe and effective? Now comes the most important part of this article. Of the 233 candidates in trials (172 in preclinical phase and 61 in some of the clinical phases) as of January 30, 2021, we have selected 4 for the moment to analyze their properties in detail. Not only because they have already been authorized for mass use or are about to be, but also because they are the most talked about. In the following table you can see a summary of them:
BioNTech-Pfizer (BNT162b2 vaccine)
Type of vaccine: first messenger RNA vaccine that has been approved for mass application in history. It uses lipid nanoparticles (LNPs) to ensure the correct release of the nucleic acid into the cytoplasm of host cells. The mRNA carries the information needed to encode the SARS-CoV-2 Spike protein and specifically its receptor binding domain (RBD), the peptide sequence that comes into direct contact with the ACE2 receptor on human cells.
Administration: intramuscular injection.
Doses: two doses of 30 µg inoculated 21 days apart.
Ingredients: in addition to the active principle (the messenger RNA molecule), it contains 4 types of lipids that constitute the lipid nanoparticles, 4 different salts that maintain the pH of the vaccine stable and similar to that of the human organism, and sucrose, a cryoprotective carbohydrate that prevents damage to the lipidic vesicle during the freezing storage. Little more, neither microchips nor sterilizing or lethal substances nor other absurdities.
Trials: 43548 participants aged 16 years or older and from different ethnic groups and countries were tested in clinical phase III between the end of July and mid-November 2020. Randomly and in a double-blind experiment, half of the participants received the vaccine and half received the placebo (control group). Several participants previously had some comorbidity (AIDS, dementia, diabetes, leukemia, liver disease, kidney disease…)
Efficacy: according to the report published in The New England Journal of Medicine, the vaccine reaches an efficacy of 95% (with a confidence interval of 90.3-97.6%) a week after the administration of the second dose. For the moment, it is known that protection is maintained for up to two months after the second injection. Likewise, in phases I and II, it was already registered a hopeful production of neutralizing antibodies and CD4+ and CD8+ T cells in young and old adults. Although this high efficacy impresses, we have to be cautious, both with the results obtained with this vaccine and with those of the candidates that we will see next. Basically, because these results corroborate that in 95% of the cases the development of the disease is prevented, but there is still no confirmation that the vaccine also prevents contagion. In other words, the vaccines could prevent us from developing the disease, but not from becoming asymptomatic carriers of the virus, and these doubts fly over all the vaccine candidates right now. If this were the case, the vaccine would only protect those who have had it, but not those around them, because it does not cut off the transmission of the virus. In any case, in view of such levels of efficacy, experts believe that the vaccine likely avoids the contagion.
In any case, the first data in this regard are already beginning to emerge and are really promising. The Clalit Health Fund, one of the most important health foundations in Israel, has included in a trial 400,000 people aged 60 or over who needed to be tested for COVID-19. Half of that population had received the first dose of the Pfizer vaccine and the other half had not. After evaluating the percentage of positives in each group, they observed that after 14 days there was a decrease in the percentage of positives of 33% in the vaccinated group, and this with only one dose. With the second dose, the probability of contracting the disease will surely be even lower. The data are preliminary and need to be cross-checked with other samples, but they certainly are a ray of hope. We will see what happens with the other candidates.
Side effects: the vaccine is quite safe. The adverse reactions it can cause (all of them transitory) are typical of any other vaccine: headaches, fever, myalgia, fatigue and body pain, erythema, and local inflammation at the injection site. Some cases of transitory lymphadenopathy were also recorded, which disappeared in 10 days. The intensity of these reactions varies from mild to moderate in the vast majority of cases and are easily treated with basic medication. Less than 4% of the participants who received the vaccine showed a severe systemic reaction after either dose (such as fatigue, severe headaches, or local pain). Further evidence of the vaccine’s safety is that there was no worsening of comorbidities that some participants previously had.
Six deaths were reported over the trial period: two among participants who received the vaccine and four among those who received the placebo. None of these events could be associated with the vaccine or the placebo. Monitoring of patient health status will continue for two more years after the administration of the second dose of placebo or vaccine.
Storage: remains stable up to 5 days in the refrigerator (2-8 ºC). However, if prolonged transport and storage is foreseen, it requires ultra-cold conservation (-60 to -80 ºC). Under these conditions, it can be kept stable for up to 6 months.
Cost per dose: it will depend on the Gross Domestic Product of each country. For example, in the U.S. it is estimated that the price will be $20, but in Africa, according to Albert Bourla, CEO of Pfizer, it will be free.
Authorized in: United Kingdom, European Union, Canada, Israel, Kuwait, Oman, Singapore, Chile, Costa Rica, Puerto Rico, Mexico and the United States (in these last two countries for emergency use only).
Questions to be answered: Is it still safe and effective beyond two months? What are its effects on population groups that are under-represented or not represented in the trials, such as pregnant women, young people under 16, allergic, and immunocompromised people? In addition to avoiding symptoms, does it also prevent transmission to non-immunized people? What will happen to people who have not received the second dose? Will two doses be sufficient or will booster doses be needed in the future?
Other information: in the United Kingdom, the vaccine has been discouraged for persons who have ever suffered an anaphylactic or allergic reaction to food, other vaccines, etc., due to two recorded anaphylactic reactions in two health care workers after receiving the vaccine. Also in Alaska, one health care worker has had an acute allergic reaction after being vaccinated. In the United States, 6 people (out of 272,000 who have already been vaccinated) have been reported to have developed allergy after vaccination. Although there is no evidence that such anaphylaxis cases were generated by the vaccine (allergy studies are needed), there is little information on how the vaccine may affect this subset of the population. In any case, the study published in The New England Journal of Medicine has not warned about any allergic reaction generated by the vaccine or its components. Anaphylaxis is generally a rare event. Pfizer and BioNTech have demonstrated this by not registering any cases during the trials and this is expected to continue (of hundreds of thousands of people vaccinated so far, less than 10 people have suffered these reactions). Even so, the main suspect is polyethylene glycol, one of the lipids that constitute the protective lipid nanoparticles of mRNA.
We must not succumb to fear. It would not be the first time that something like this happens. For example, flu vaccines are usually contraindicated in people with strong allergies to eggs, since embryonated eggs are used in their production process. However, this is quickly solved by reducing the concentration of egg proteins.
Moderna-National Institute of Allergy and Infectious Diseases (NIAID) (mRNA-1273 vaccine)
Type of vaccine: mRNA vaccine encoding for the Spike protein included in a lipid nanoparticle.
Administration: intramuscular injection.
Doses: two doses of 100 µg inoculated 28 days apart.
Ingredients: messenger RNA, 4 different lipids that make up the protective vesicle of the nucleic acid, tromethamine, tromethamine hydrochloride, acetic acid, sodium acetate (these four substances are pH stabilizers, among other things) and sucrose (same function as in the Pfizer vaccine)
Trials: tested in approximately 30000 adults aged 18 years or older of different ethnicities in double-blind, randomized, placebo-controlled trials.
Efficacy: the vaccine’s efficacy is estimated at 94.1% from the study of 196 cases of infection analyzed from the second week after the administration of the second dose. 185 of these cases occurred in the control group and only 11 in the vaccinated group, hence the estimate. Efficacy may vary as more case studies are included, but not by much. No cases of severe COVID-19 were observed in the experimental group and 30 in the placebo group. Among all those patients, 15 were over 65 years old. The study population also includes thousands of patients with various comorbidities and high risk people (diabetes, severe obesity, cardiovascular disease, AIDS).
Side effects: serious adverse reactions are rare, although slightly more than in the Pfizer vaccine, especially after the administration of the second dose: fatigue (9.7%), myalgia (8.9%), headache (4.5%), pain at the injection site (4.1%), erythema (2%). Even so, the frequency of severe adverse events was very reduced and similar between the placebo and the vaccinated groups (1.3 and 1.5% respectively). Five people died during the trials: 3 in the placebo group and 2 in the vaccinated group, although no deaths were related to the trials. The follow-up of the patients will last 2 years since the application of the second dose.
Storage: 12 hours at room temperature, 20-30 days in the refrigerator (2-8 ºC) and up to 6-9 months in the freezer (-20 ºC).
Cost per dose: 24 – 40 $.
Authorized in: United States for emergency use only, Puerto Rico, Canada, European Union, United Kingdom.
Questions to be answered: similar to the ones above: How long does the immunity last? How does it affect pregnant women, immunocompromised persons, and young people under 18? Will it also prevent infection and transmission to non-immunized persons? Will more booster doses be neeed?
University of Oxford-AstraZeneca (ChAdOx1-S vaccine)
Type of vaccine: recombinant attenuated (non-reproductive) chimpanzee adenovirus vaccine used as a vector for the SARS-CoV-2 genes that synthesize the Spike protein.
Administration: intramuscular injection.
Doses: two doses inoculated 28 days apart.
Ingredients: have not transcended yet.
Trials: tested on more than 24000 people age 18 and older and of different ethnicities in randomized single- and double-blind studies between April and November 2020. More than 200 participants were 70 years or older. Some had co-morbidities such as diabetes, respiratory, and cardiovascular diseases. The control group was inoculated with a saline solution or a meningococcal vaccine. Tests were conducted in the United Kingdom, South Africa, and Brazil. In the experiments in South Africa and Brazil, participants were inoculated with two standard doses (5×1010 viral particles). However, in the UK phase 2/3, participants accidentally received a first dose of lower concentration and a second of standard concentration.
Efficacy: 62% when two standard doses were administered (and taking 98 cases of COVID-19 as a reference) and 90% when a first low dose and a second standard dose were applied (estimated from 33 cases of COVID-19). Both results were observed 14 days after the application of the second dose. Combining both scenarios, an efficacy of 70.4% was obtained (with 131 cases of COVID-19 analyzed). The stimulation of T cells and neutralizing antibodies was registered. Older people show a hopeful immunogenicity and tolerance to the vaccine. No cases of severe COVID-19 were found in the vaccinated group.
Side effects: similar to the previous cases, both in category (local and systemic effects) and in intensity. No severe adverse reactions associated with the vaccine were registered. Three cases of transverse myelitis were reported during the trials period. The trials were temporarily stopped until it was proven that the vaccine was not the cause. Independent teams of neurologists have concluded that none of the cases are due to the vaccine. A Brazilian participant died during phase 2/3, but belonged to the placebo group.
Storage: in the refrigerator (2-8 ºC).
Cost per dose: due to its easy production and storage, a price of 3 – 4 $ is estimated, although it could increase by 20% or more by contract.
Authorized in: United Kingdom, European Union, Brazil.
Questions to be answered: similar to the ones above.
Gamaleya Research Institute of Epidemiology and Microbiology (Gamaleya Gam-COVID-Vac/Sputnik V)
Type of vaccine: is the first COVID-19 vaccine registered in the world. It is a recombinant attenuated (without capacity to reproduce) vaccine of human adenovirus (it uses two different adenoviruses, one for each dose, to avoid that the second dose is neutralized by the immune system in case it recognizes again the same type of adenovirus) used as vector of the SARS-CoV-2 genes that synthesize the Spike protein.
Administration: intramuscular injection.
Doses: two doses inoculated 21 days apart.
Ingredients: have not transcended yet.
Trials: tested in over 40000 people aged 18 years or older (including people over 60 years old) in double-blind, randomized, placebo-controlled trials.
Efficacy: according to preliminary results, an efficacy of 91.4% has been estimated at 21 days after the inoculation of the first dose in the last control made. The researchers declare that, from day 21 to day 42 after the administration of the first dose, the efficacy increases to 95%. However, this estimate has been obtained from 39 cases with COVID-19 only. It also appears to prevent severe COVID-19 in 100% of cases. No peer-reviewed studies have been published yet. It would generate both humoral and cellular immune responses.
Side effects: no serious or unexpected adverse reactions were recorded, only the typical ones.
Storage: the freeze-dried form remains stable in the refrigerator (2-8 ºC) and the non- freeze-dried form at -18 ºC.
Cost per dose: less than 10 $.
Authorized in: Russia, Argentina and Hungary.
Questions to be answered: similar to the ones above.
Other information: on December 11, AstraZeneca announced that, along with the Russian vaccine, they would begin testing a combination of both on candidates 18 years of age or older to assess whether that combination generates a stronger immune response than they do separately. The goal is to use a different adenovirus vector (the chimpanzee adenovirus and the human one) at each dose. This is expected to have a greater effect than administering the same adenoviral vector in both doses. In fact, it is speculated that this factor would have been responsible for the reduced efficacy of the vaccine of AstraZeneca and Oxford: it is possible that the immune system generates a certain memory against the adenovirus, so that when the same adenovirus is inoculated with the second dose, it generates a rapid secondary immune response that partially neutralizes the action of the vaccine.
There are a number of indications specified, among others, by the U.S. FDA for the Pfizer and Moderna vaccines which will surely be applied to the rest of the vaccines in the U.S. and the rest of the world. Among them, it should be noted that the vaccines are expressly contraindicated for persons who may suffer anaphylaxis against any of the vaccine components or who suffer anaphylaxis after receiving a dose of the vaccines. To avoid unnecessary risks, it is recommended that persons that will be vaccinated should report in advance any medical condition of interest: any allergies, pregnancy or plans to become pregnant soon, bleeding disorders, or anticoagulant medication, if they have a fever or are breastfeeding, if their immune system is compromised by a disease or medication, and if they have previously received another type of COVID-19 vaccine. Moreover, even though some countries have decided to space out doses or mix different COVID-19 vaccines, these actions are also contraindicated.
- Novavax (NVX-CoV2373 vaccine)
Type of vaccine: it is a subunit vaccine that uses nanoparticles of the coronavirus’ spike protein with small mutations to ensure its stability obtained by recombinant technology. It is accompanied by the saponin-based Matrix-M1 adjuvant, manufactured by Novavax, to enhance the production of neutralizing antibodies.
To make the proteins, its genes are recombined with the genome of a baculovirus, a DNA virus specialized in infecting invertebrates. Subsequently, this virus-vector is forced to infect a culture of moth cells, which will be responsible for synthesizing the spike proteins of the coronavirus. Finally, these proteins are purified, subjected to a series of treatments and assembled to form the nanoparticles that will make up the vaccines.
Administration: intramuscular injection.
Doses: two doses of 5 µg of antigen + 50 µg of adjuvant inoculated 21 days apart.
Ingredients: have not transcended yet.
Trials: Phase III has been tested in the UK with over 15,000 people aged 18-84 years in double-blind, randomized, placebo-controlled trials (some cohorts were inoculated with saline solution and others with seasonal influenza vaccine). Twenty-six percent of the participants were over 65 years of age.
We will also mention the Phase b2 trials carried out in South Africa with more than 4,400 people and the trials in Mexico and the United States, in which people are being recruited to reach 30,000 participants to initiate the Phase III. The characteristics of these trials are similar to those in the United Kingdom (double-blind, randomized and placebo-controlled).
Efficacy: according to an announcement (a peer-reviewed study has not yet been published), the preliminary results of Phase III in the United Kingdom indicate an efficacy of 89.3% at 7 days after the second dose. This was calculated from 62 cases of SARS-CoV-2 infection, 56 in the placebo group and 6 in the vaccinated group. This is the first study to test the efficacy of a vaccine against the British variant of the coronavirus, since more than half of the 62 infected people were infected by the variant. An efficacy of 85.6% was obtained against it (preliminary results).
Efficacy is reduced for the South African variant of SARS-CoV-2. Forty-four cases of infection were detected in the South African trials, although 27 cases have been sequenced by PCR so far. Of these, 92.6% have been infected by the South African variant. Overall, a preliminary efficacy of 49.4% was obtained, but it should be noted that 6% of the participants had HIV. The vaccine efficacy in the HIV-negative population amounted to 60%.
Previous studies have shown the production of neutralizing antibodies and CD4+ T lymphocytes.
Side effects: Severe adverse reactions are anecdotal so far. In earlier phases (with fewer participants), mainly mild to moderate effects were observed, especially after the second dose, such as local pain, fatigue, headaches, myalgia or general malaise.
Storage: stable at 2-8 ºC.
Cost per dose: about $16.
Authorized in: nowhere yet.
Questions to be answered: similar to the ones above.
Other information: Novavax will immediately begin the development of a vaccine specific for the South African variant to counteract the poor efficacy of the current vaccine. Fortunately, since only a small amount of antigen is used due to the adjuvant, it will be possible to manufacture and produce large quantities of vaccine variants in a short time.
- Janssen Pharmaceutical (Ad26.COV2.S vaccine)
Type of vaccine: it uses a recombinant attenuated (it cannot replicate) human adenovirus (serotype 26) that carries the genes for the synthesis of the SARS-CoV-2 Spike protein.
Administration: intramuscular injection.
Doses: a single dose of 5*10^10 viral particles.
Ingredients: have not transcended yet.
Trials: for Phase III, still ongoing, 60,000 participants aged 18 years or older and from different regions are intended to be recruited for a double-blind, randomized, placebo-controlled trial. As of January 30, 2021, 44,325 people have been recruited. The results we are going to present were obtained from 43,783 participants. Thirty-four percent of the participants were over 60 years of age and 41% had comorbidities that can worsen the diagnosis of COVID-19.
Efficacy: the company has announced that its vaccine prevents 66% of moderate and severe cases of COVID-19 (they are preliminary results as the trials will continue for 2 more years and have not yet been published in any scientific journal). On the other hand, considering only the most severe cases, this vaccine prevents them 85% of the time. This protection would be reached 28 days after vaccination, although it begins to develop 14 days after the administration of the dose. After 49 days, severe cases of COVID-19 were no longer observed.
In different regions where trials are being conducted, different efficacies have been obtained: 72% in the United States, 66% in Latin America, or 57% in South Africa (variations possibly due to coronavirus variants). In South Africa, 95% of the infections tested were due to the South African variant.
The protection offered by the vaccine is to some extent consistent across all “races”, age groups, regions studied, and SARS-CoV-2 variants, although protection appears to be reduced against the South African variant. Furthermore, the data suggest that people with certain comorbidities may also be protected against the worsening of their conditions if they become infected.
The stimulation of CD4+ and CD8+ T lymphocytes and neutralizing antibodies has been registered.
Side effects: they state that serious effects are rare (e.g., they detected Grade 3 fever in 0.2% of cases). They also state that no anaphylactic reactions have been observed so far.
Storage: it remains stable for 3 months at 2 – 8 ºC and for two years at -20 ºC.
Cost per dose: estimated to be below $12.
Authorized in: nowhere yet.
Questions to be answered: similar to the ones above.
Other information: in parallel to this trial, Janssen is testing the efficacy and safety of the vaccine administered in two doses 57 days apart.
The difficulties of distribution
Imagine that we already have the ideal vaccine ready to be administered to the population in order to achieve herd immunity. Who do we start with? The groups at risk most likely to contract the disease and/or develop the most serious variant or those who are most contagious? Bear in mind that, at the beginning, the supply will be very limited, so we must clearly decide who will be the first.
As expected, there is a heated debate in this regard, although there is consensus on some points. For example, it is common sense that one of the first groups to be immunized must be health care workers. Not only because they are too exposed to the pathogen, but because they are the first and most important line of defense our civilization has against the pandemic.
The ACIP, the Advisory Committee on Immunization Practices, a committee of experts that advises the U.S. Centers for Disease Control and Prevention, believes that in a scenario where vaccine supplies are limited, the first to be vaccinated, in addition to health care workers, should be essential workers of critical infrastructure sectors (those who ultimately maintain the balance of society by ensuring the supply of clean water, electricity, communications, energy…) and people at high risk because of comorbidities and/or their age (over 65). This could be a first phase of vaccination.
If we consult the criteria of the US National Academies of Sciences, Engineering, and Medicine, the second phase would include teachers (education is another fundamental pillar of all societies), people at moderate risk, prison staff and prisoners, the homeless, staff of mental health centers and patients of such centers… Young adults and children would be vaccinated in phase 3. Finally, all those not included in the previous phases would enter in phase 4.
Therefore, authorities try to follow a protocol that gives priority to the health of the population and the economy, while at the same time try to ensure that all people, regardless of their socioeconomic class, have access to vaccines. These criteria are also followed in other countries. In Spain, for example, health and personal care personnel, high-risk people, people at risk due to their socioeconomic situation, teachers, etc., will also have priority access to vaccines.
Apparently, these strategies would make sense… But are they correct? What happens if we continue to fail to control the famous asymptomatic and healthy “superspreaders” who, precisely because of their state of health, will be the last to be vaccinated? Indeed, otherwise lives are saved, but the virus can continue to spread uncontrollably. For this reason, many consider that, in order to stop the pandemic as soon as possible, the first batches of vaccine should also be destined to the groups with the greatest capacity to spread the virus (young adults, for example).
Be that as it may, vaccination plans are loaded with good intentions trying to ensure democratic and broad access to all people. However, in practice this is difficult to achieve. If countries like the United States have a basic health coverage that is difficult for people with scarce or moderate economic resources to access, will those people really be able to access the vaccine so easily? It is possible that the administrations will organize well, for example, by distributing the vaccine free of charge as some have already suggested… But what about the rest of the countries? Once again, we are naive. Nations are bent on immunizing their respective populations as soon as possible, without taking into account the surrounding nations. Countries that may not have the same capacity as their neighbors to access millions of doses, taking much longer for them to achieve the herd immunity. Once again, it would be a serious mistake to ignore the globalized society in which we live, a lesson that SARS-CoV-2 is forcing us to assimilate.
We are constantly interconnected. What is the point in a globalized world to focus immunization on specific areas? Isn’t it better to achieve a more global and widespread immunity as soon as possible? It’s complicated, especially in the beginning, when vaccine doses are going to be very limited. But let’s think of a theoretical scenario that, why not, could take place. Some specific countries are determined to achieve the immunization of their respective populations and the rest cannot or are further behind because they have later and limited access to the vaccines. In the latter, the virus continues to spread freely, spreading through large numbers of unimmunized people… and mutating. What if a SARS-CoV-2 mutation emerges in some of these places and makes the vaccines useless? It is one of the worst fears, that everything will go wrong because a new variant of the virus will emerge. So we see the enormous challenges that our global society faces in dealing with this pandemic.
I want to dwell a little more on this reflection, because the (greedy) actions of some countries can complicate the equitable access (at the international level) to vaccines. It did not take long for the United States, the United Kingdom and others to reserve millions of doses of different vaccines for themselves as soon as the first positive results on these vaccines were published. Logically, these countries can do that without too many problems because of their enormous purchasing power. But what about poor countries or regions that are also usually the ones with the highest population densities on the planet? This creates competition for vaccine supply.
But let’s look at more factors. Some of the vaccine candidates have to be refrigerated at extremely low temperatures, and that requires very sophisticated and complex infrastructures. How many countries in these regions have the means to maintain the cold chain for the vaccine until it is administered? In addition, the warm climate in some of these regions is an added challenge. This can greatly complicate the distribution. Not only that. The more complex the vaccine is (in terms of production, processing, transport and storage), the more expensive it will be. For the most needy countries, the cost of $1 per dose is already difficult to afford. Imagine, therefore, the difficulties of these countries to acquire the necessary doses to vaccinate millions of people.
In the face of economic obstacles, some have already begun to take the first steps towards solving them. For example, the CEO of Pfizer, Albert Bourla, declared in a press conference that the price of his vaccine will be staggered and will vary depending on the Gross Domestic Product of each country. That is to say, while in the United States the dose will be sold for 20$, in India it will be commercialized for less and in Africa, according to the executive, it will be free. On the other hand, there is a petition directed to the World Trade Organization to suppress the patents on COVID-19 vaccines at least for the duration of the pandemic in order to facilitate access to them and lower their cost. That kind of decisions can mark the success against the pandemic by promoting equitable multinational access.
Another drawback to be solved is the achievement of the herd immunity. It is estimated that, to defeat the pandemic, more than 60 or 70% of the population needs to be immunized. To do this, we need to have multiple factories that are capable of supplying billions of doses per year if we want to overcome this situation in a short period of time. To give an example: Pfizer has assured that, through its combined network of facilities, it will manufacture 1.3 billion vaccines by 2021. Will it be able to do so, or is this a propaganda stunt?
Let’s take a look at a much smaller scale to get an idea of how long it can take to ensure the herd immunity against a disease. In India, one of the most ambitious vaccination programs ever launched aimed to immunize 403 million children against measles and rubella. It took three years to achieve it. That’s just in India, one of the most overpopulated countries in the world. How long will it take to achieve global immunity?
The only way to tackle this pandemic, as history has repeatedly shown, is to overcome the threshold of herd immunity, and for that, solidary and well-organized vaccination campaigns are unfailingly needed. The alternative of achieving this immunity in a “natural” way, that is, by allowing the virus to disperse so that the population obtains immunity through contagion, is hardly contemplated at present. And in any case, if it is contemplated it is like a suicide. As I say, history has already given us several lessons in this regard. As virologist Angela L. Rasmussen points out, take polio or smallpox, for example, which have been infecting the population tirelessly for centuries. However, the seroprevalence of these pathologies has not even come close to the threshold needed to achieve collective immunity. Instead, it is only when the vaccines arrived that we managed to either stop them (in the case of smallpox) or reduce them to a few marginal cases. The same is happening with SARS-CoV-2. Seroprevalence levels, even though tens of thousands of people are infected every day, are still only 10% in Spain or 20-25% in the most affected states of the United States, such as New York. And that’s not counting the strains that can cause reinfections and that skip the immunity stimulated by previous strains.
Equating the immunity obtained from SARS-CoV-2 infection and from vaccination means accepting that the two are the same, but that is not the case. There is already evidence that SARS-CoV-2 is capable of sabotaging the immune system. A percentage of the people affected by the severe variant of the disease have the interferons type I and III suppressed, a group of cytokines in charge of modulating the immune response so that it does not overflow. When they fail, the much-feared and potentially lethal cytokine storm may occur. But not only that, because this virus has many strategies to neutralize the immune system and its memory. Autopsies of some patients who have died from COVID-19 are revealing cases of lymphopenia (low number of lymphocytes) resulting from the infection. Specifically, some of these people had a shortage of CD4+ and B lymphocytes and a loss of germinal centers in the lymph nodes (the places where these cells are born). This implies that the immune memory (so important to ensure prolonged immunity) generated by these cells could be at risk. Vaccines, on the other hand, since they do not cause the infection as such, can avoid all these problems and ensure a more effective and longer lasting immunity.
Unfortunately, human beings are animals of habit. If we have lowered our guard the moment we knew that infections were decreasing, everything indicates that we will do the same during the vaccination period. And yet we will make another serious mistake, putting the health of the society and our own at risk. Even if we have vaccines, we cannot abandon the rest of the prophylactic measures. For various reasons: firstly, the first vaccines that have been approved require two doses to achieve strong immunity. These doses are administered several weeks apart, during which time we will not be completely protected. We don’t know for sure if the vaccines will be able to stop the transmission of the virus or if they only prevent the symptoms of COVID-19. If, unfortunately, that were the case, vaccinated people could become asymptomatic focal points of infection. Let’s also consider that no vaccine will be 100% effective, that is, a tiny percentage of people will still be vulnerable to the virus even if they have been vaccinated. There are, therefore, several reasons not to lower our guard and continue to wear a mask, maintain minimum safety distances and avoid crowding. The unfulfilment of these basic standards constantly increases the likelihood of sabotaging ourselves. The more we facilitate the spread of the coronavirus, the more opportunities it will have to mutate into new strains and variants, some of which could nullify the vaccines. And although these are generalist (they are made to work well against a wide range of variants and strains of the virus, as the immune response is stimulated by several elements at once) and mouldable (mRNA vaccines, for example, could be remade in a few weeks if they lose effectiveness against a new strain that has undergone significant changes in its Spike protein), we shouldn’t tempt fate.
There are still many unanswered questions about vaccines. Even so, the results that have been published so far are very positive and encouraging. This alone should encourage us to get vaccinated. After all, almost all vaccines that end up being authorized have shown that the balance between their risks and benefits is clearly tipped towards the benefits. On the other hand, we are surely experiencing a new turning point in human history as we have managed to develop effective and safe vaccines in record time. Preventive medicine is going to undergo a major evolution from now on, not only because of the new vision we will acquire regarding vaccine development protocols, but also because of the new versions that are going to be marketed for the first time in history, such as messenger RNA vaccines.
Amidst the blackness and pessimism surrounding the pandemic, there is a glimmer of hope. We will gather lessons on how to deal with a pandemic in the context of a globalized society. We will gain new tools to fight coronaviruses and other pathogens that we have previously considered elusive. And I hope we will finally learn to recognize the true value of the global society, of living in harmony with ourselves and others in order to strengthen the bonds that bind us all.
It is science that points the way to the light that awaits us at the end of the tunnel. Let’s hope that this sad episode will make us reflect and learn to value it as it deserves. Because science, the same that is furiously attacked by ignorance and radicalism and that, in contrast, manages to save 3 million lives annually through, for example, vaccines, will be the one that will solve all our problems… again.
If you want to know in detail how the different types of COVID-19 candidate vaccines work, read the first part of this series:
The SARS-CoV-2 vaccines. Part 1: The mechanisms of vaccines
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