Santiago Herrero, MD
THE COVID-19 VACCINE? NOT BEFORE A YEAR AT LEAST, IF EVERYTHING WERE DONE RIGHT
If several days ago Pfizer-BioNtech announced its vaccine (RNA type x 2 doses) that it is 90% effective and has revolutionized the world, two days later Russia announced that its Sputnik (Gamaleya) vaccine , (Viral vector with genetically modified virus) is 92% effective: 2% higher than that of Pfizer.
Yesterday Moderna (RNA type with part of virus genetic code and x 2 doses), another vaccine made in the US announces that its efficacy rises to 94.5% and also does not need conservation at very low temperatures like Pfizer’s (around -80º C), which adds a competitive advantage. Another in the game is the vaccine of Oxford UniAstra Zeneca (Viral vector x 2 doses) still on Phase III.
As I said a long time ago, we are now in the data war. Each one will be better than the previous one, and will come with different characteristics. This really raises doubts about each one of them, given that a manipulation of intermediate data could be a commercial strategy and more in sight than even without definitive results, the stock market rises of the pharmaceutical companies also skyrocket as in the case of the CEO (CEO) of Pfizer managed to sell his shares for a few million dollars.
Not only do we have to suffer this pandemic, it is that now we also have to suffer the trade war between countries for their vaccines. “What makes the Russian vaccine special is the use of two different human adenoviral vectors that provide a strong and lasting immune response after the second injection”, they say. Those from the USA, which can be kept in a normal cold station and not large high-freezing containers. It is true that any vaccine with an advantage greater than 90% in immunizations could be considered effective and that with them it would be worth to be included. But we lack data such as the number of patients included in phase III and side effects as well as the real data between placebos and vaccinated, given that these studies are carried out by the double-blind method (it means that neither the patient receiving, nor the doctor who administers it knows if it is a real vaccine or it is the placebo or a harmless substance). But there are lights that say that this methodology is not being clearly carried out and of course until they are published these clearly commercial exclamations should not be launched.
They speak of success without having final data, they are simply intermediate analyzes.
I said it a long time ago, running a lot does not mean arriving earlier, since you can make mistakes and a miscalculation can ruin any business matter. Vaccine manufacturers must also commit to adhere to high scientific and ethical standards in conducting clinical studies and in manufacturing processes. So watch out for results that are intermediate.
A total of 172 countries and multiple vaccine candidates are part of the Global Access Mechanism for Vaccines against COVID 19
The development of the vaccine generally takes years, however, in the case of drug trials against Covid-19, they are progressing at an accelerated rate, as companies and countries are urged to stop the spread of the virus. coronavirus. Let’s see, if the normal process for making a vaccine varies between 5 to 10 years, can such predictions be made? Obviously our President of the Government has no idea and I imagine he allows himself to be endorsed because certain scientists say that for COVID 19 they now estimate that they will be able to obtain a vaccine in just 12 to 18 months.
Why does this say? From China they said at the beginning that they were very optimistic, but they realized that this could not be the case. Words not to spread panic, which many other politicians made their own, including ours. But these optimistic words are nothing more than empty words, full of political contention, in the face of the disaster that was coming. I am not so optimistic, especially because, for example, the HIV / AIDS virus known since 1983 has not yet arrived any vaccine and that we have the most impressive technology at the moment.
What is the difference between the AIDS virus with this virus and the influenza virus, including influenza A H1N1 and H5N1 or avian?
The first thing that are viruses of different origin. There are several classifications of viruses, the last one was given in 1971 (David Baltimore) and that classifies them from one to seven groups depending on a combination of their nucleic acid (DNA or RNA), chain (single-stranded or double-stranded), sense and method of replication.
The human immunodeficiency virus (HIV) was discovered by Luc Montagnier in France in 1983. It is a lentivirus (retrovirus family) that causes HIV infection (Group VI: reverse transcribed single-stranded RNA virus). The drugs that control it are called antiretrovirals. There is no current vaccine.
The flu was first identified in Italy in 1878. But 100 years ago, the so-called Spanish Flu was born in the US and spread to Europe. It arose in a Kansas county since the strain was H1N1 or swine flu, where it affected a military base (Fort Riley) on March 18, 1918. The devastating voracity of this virus affected almost a third of the human population, that is, 500 million people, killing about 100 million people. This pandemic caused more deaths than World War I and World War II combined. Influenza (influenza) is a contagious respiratory disease caused by RNA viruses of the Orthomyxoviridae family (Group V: RNA, single-stranded negative). The virus was isolated in 1930, and what has rained since then.
But there are also different strains, among them the famous H1N1 or known as influenza A or swine (which is the same as the Spanish flu of 1918, the one of 1970 and the most recent one in 2009, which caused more than 500,000 deaths and affected 12% of the population).
The vaccines that began to be monovalent in 1940 and are now tetravalent (that is, for at least four strains of the same virus, given the mutations of the same).
Avian influenza H5N1 virus (1) is another RNA virus of the Orthomyxoviridae family (Group V: RNA, negative single-stranded) and that has the same similar tropism (meaning it likes the respiratory epithelium) to the rest of influenza viruses or as that of SARS-Cov-2. The induction mechanism is somewhat different because it does not use the known expression system ACE2 or the new neuropilin-1 in addition to other proteins under study such as CD147 which could suggest that an antibiotic already used such as Azithromycin could work because it has not been known this other method of expression.
In 2005, the complete sequencing of the genome of the pandemic influenza virus H1N1 (of the 1918 virus) was carried out. On April 17, 2009, the new H1N1 virus is detected in the United States and it is not until April 25 that the WHO declares a public health emergency of international concern and later on June 11, 2009 the WHO officially declares a pandemic to the outbreak of the new H1N1 virus. This is where the rapid diagnostic tests by PCR begin to arrive and then the antigens. Oseltamivir (Tamiflu) treatments significantly reduced the disease, but they are not vaccines but antivirals.
It is not until October 5, 2009, when the first dose of the monovalent H1N1 virus vaccine is administered, all after 4 years of studies, although the pandemic certainly accelerated the entire previous process. The WHO declared the H1N1 pandemic ended in 2010, but there have been outbreaks in subsequent years in many parts of the world, the last being in Malta, Morocco and Iran during 2019.
What happened to the SARS virus (acute respiratory syndrome virus) in 2002 and the MERS virus (Middle Eastern respiratory syndrome) in 2010? These two viruses (group IV: coronavirus, positive single-stranded RNA) have a genome resemblance to the current SARS-CoV-2 by 96%, which is a lot, but we have not had vaccines despite being widely studied during these years, although both behaved radically differently both in its control and in its transmission.
The MERS virus still has an impact in the Middle East. When I worked in Saudi Arabia in 2015, the treatment of every patient who came to the ICU for a respiratory condition included Tamiflu and it is still used regularly. The process of making a vaccine is very complicated and nothing is quick. It is estimated that between its inception until production and distribution it lasts much more than 2 years. Unimaginable resources are being used in this pandemic, but times are times and no matter how long it takes, it is not possible to reach the final stretch in at least 18 months.
Why at least 18 months and not 2 to 4 years?
Simply because the information about the virus and the arrival of the viral genome was fast (from the first case in December 2019 to January 10, 2020, which means less than a month). Once the genome is known, developing the process occurs in different studies.
The complete list of candidate vaccines supported by CEPI (Coalition for the Promotion of Innovations for Epidemic Preparedness) is as follows (2):
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Inovio (USA) (phase I / II)
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Modern (US) (phase III)
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CureVac (Germany) (phase I)
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Pasteur / Merck / Themis Institute (France / USA / Austria) (preclinical phase)
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AstraZeneca / University of Oxford (UK) (phase III)
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University of Hong Kong (China) (preclinical phase)
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Novavax (USA) (phase I / II)
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Clover Biopharmaceuticals (China) (phase I)
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University of Queensland / CSL (Australia) (phase I)
Other vaccines such as Pfizer (phase III) are not financed by public agents due to commercial strategies and possible interference from the public and from international organizations or governments. The Sputnik vaccine is endorsed by the Russian Government. Then there are many other independent ones and each country is developing its own vaccines.
As of June 30, 2020, the U.S. Food and Drug Administration (FDA) took important steps to help facilitate the timely development of safe and effective vaccines to prevent COVID-19 by providing a guide with recommendations for those who are developing vaccines against COVID-19 with the ultimate goal of obtaining a license.
The guide, which reflects the advice that the FDA has been providing in recent months to companies, researchers, and others, outlines the agency’s current recommendations regarding the data needed to facilitate production, clinical development, and approval. of a vaccine against COVID-19.
The European of Drugs Agency also in the current pandemic will provide and facilitate guidelines to obtain a license.
The published guidance, “Vaccine Development and Licensing to Prevent COVID-19,” provides a summary of key considerations for meeting chemical, production, and control requirements, and clinical and non-clinical data across the development and licensing, and for post-licensing security assessment. Importantly, given current knowledge of SARS-CoV-2 immunology, the goal of development programs, at this time, should be to support traditional FDA approval by conducting studies to directly assess the vaccine’s ability to protect humans from SARS-CoV-2 infection and / or disease. The FDA strongly recommends the inclusion of diverse populations in all phases of clinical development, including populations most affected by COVID-19, specifically racial and ethnic minorities, as well as adequate representation in the later phase of older people and people with medical comorbidities.
Sponsors are also encouraged to include studies in their development plans that can provide data to support use during pregnancy, as well as plan for pediatric safety and efficacy evaluations. The guide also addresses the importance of ensuring that clinical trial sizes are large enough to demonstrate the safety and efficacy of a vaccine. It is understood that the FDA hopes that a vaccine against COVID-19 would prevent the disease or reduce its severity in at least 50% of the people who are vaccinated.
These are the different phases 1.- Laboratory Phase2.- Clinical phase. Security tests: Here come the different phases of biosecurity known as Clinical trials
- 1.- An antigen is generated. Viruses are grown in primary cells (in this case not in chicken eggs like the flu virus) with bronchial epithelial cells using a basal medium that promotes cells.
- 2.- The antigen is isolated from the cells that were used to create it.
- 3.- Vaccine process. Adjuvants increase the immune response of the antigen, stabilizers increase the duration of the vaccine and condoms allow the use of ampoules with various doses.
3.- Licensing phase: Regulation and commercialization process 4.- Production phase 5.- Distribution phase
- Phase I (Safety and immune response)
- Phase II (safety, immunogenicity and proposed dose)
- Phase III (Safety and efficacy in the study population group)
All this can last at least 18 months (minimum) but the problem does not end there. In many cases, vaccines fail to reach their final stage, since the virus mutates and you have to start over.
Mutagenesis: That is a process by which an organism’s genetic information is changed, resulting in a mutation. It can occur spontaneously in nature or as a result of exposure to mutagens. It can also be achieved experimentally by laboratory procedures. The mutation causes the appearance of new strains. Up to at least 7-8 strains of the coronavirus are known from SARS and MERS. Since the pandemic was made public on March 12, 2020, up to 8 vaccines have already begun to be studied.
But they all started with the Genomic strain D614 and since then several different strains have come out due to mutations. Of the first large outbreak with the highest mortality in Europe and America, this strain is different from that presented in China and other parts of Asia with a mortality of around 3-4%. The one presented in Europe with mortality between 8-12% is different from the initial one. The second outbreak is a G614 strain that, unlike D614, is much more infective or morbid but less fatal. The problem is that despite being less fatal as it affects more people, the number of deaths will increase. It is unknown whether this variant will be covered by the vaccines.
The coronavirus strain discovered in Spain
In a prepublication on October 28 (3), Swiss and Spanish researchers report that a strain of the new coronavirus originated in two massive superpropagation events that occurred in Aragon and Catalonia and that it later spread to Valencia, from where it spread to the rest of the world. country. Because the European borders were opened in July, thousands of Spaniards and tourists from other countries traveled to Spain, where they were infected with the Spanish variant of the new coronavirus, baptized as A20-EU1, and carried the virus back to their countries of origin.
Thanks to genome analysis and phylogenetics, the researchers showed that this A20-EU1 variant spread rapidly in Europe, and came to represent the:
- 90% of UK sequences,
- 80% of sequences in Spain,
- 60% of the sequences from Ireland and
- Between 30 and 40% of the sequences in Switzerland and the Netherlands.
This makes this variant currently one of the most common in Europe. The A20-EU1 has also been identified in France, Belgium, Germany, Italy,Latvia, and Sweden, And it has reached Hong Kong and New Zealand.
The study authors clarify, however, that this does not indicate that the current second European wave is caused by the Spanish variant. Another important clarification is that the fact of finding this variant does not indicate that a special vaccine against that strain is needed. What happens, that unlike the beginning of the pandemic, mortality can vary between countries.
The one we had in March is no longer the same as in October. If now perhaps it is less deadly but more infectious and transmissible, which means it is much more morbid. This is what happens with the vaccine against HIV, a virus that changes continuously and that is why to date a vaccine for the AIDS disease has not been achieved.
How does mutagenesis affect vaccines?
Well, almost everything. This will slow down all the processes because they have start over and will also create at least bivalent vaccines (covering at least two strains). Our Spanish President says that in May 2020 there are vaccines (a word that does not say if it will cover the population or a part), but I think not. My personal vision tells me that I don’t see it for a year. The problem is the mutation of this virus, it will change everything. Now that if they want to vaccinate us and leave us exposed to variants, that is another matter.
DISCLOSURE The author has no conflict of interest in this publication
REFERENCES
1.- Casillas, S.; Herrero, S. Varon, J. Bird flu: what the intensivist must know. Med. Intensiva [online]. 2008, vol.32, n.4, pp.183-193. ISSN 0210-5691.
http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S0210-56912008000400006&fbclid=IwAR2o18Qt6IkoipqvCYlISQNJc2gc_LFPkv4rq1BTlST1qxOm7ulQ57wEBrM
3.- Emma B. Hodcroft,ET AL. Emergence and spread of a SARS-CoV-2 variant through Europe in the summer of 2020 (Pre print) https://www.medrxiv.org/content/10.1101/2020.10.25.20219063v1.full.pdf
The Journal of Pearls in Critical Care, Twitter: @drsherrero
CITATION
Herrero S. “COVID-19 vaccine: the war has begun”. The Journal of Pearls in Critical Care. Noviembre 2020 Vol. 72. Link: https://wp.me/p19kQl-UB
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