In this article we will provide some guidelines to learn a little more about the different vaccines that exist in the world to combat the largest global pandemic recorded in recent decades.

Originating in China in late 2019, it quickly spread around the world in a matter of weeks and almost no country was exempted from its virality.
To date, only a handful of countries on the globe are free of the virus: Palau, Naurau, Kiribati, Tuvalu and Tonga, all of them island and located on the Pacific Ocean.

The first predictions

In April 2015, Bill Gates, founder of Microsoft and the third richest man in the world, warned that the next disaster that would occur in the coming decades would not be due to nuclear wars, but to a pandemic.
And more specifically, that caused by a virus.
“We are not ready for the next epidemic,” he said in a TED talk.
Four years later, his words became a reality.

Bill Gates: “If anything kills over 10 million people in the next few decades, it’s most likely to be a highly infectius virus, rather than a war.”

Is Bill Gates a visionary?
Does he use supernatural powers to make these kinds of predictions?
The answer is no.
His observation is based on the huge budgets that governments around the world allocate to nuclear weapons, rather than to investment in public health as well as research and development.

What is SARS-CoV-2?

Coronaviruses (CoV) in the broad sense are a group of single-stranded enveloped RNA viruses.
These belong to the subfamily Orthocoronavirinae, family Coronaviridae, in the order Nidovirales.
They are classified into four genera: alpha, beta, gamma and delta coronavirus.
The first two can infect humans.
They are pathogenic agents that can be transmitted to animals and humans and have a worldwide distribution.

https://revistas.udea.edu.co/index.php/iatreia/article/view/341260

SARS-CoV-2 is an enveloped virus consisting of a positive-sense single-stranded RNA genome of around 30 kb.

The history of SARS-CoV-2 or more commonly known as coronavirus, which causes the COVID-19 disease, could have started in an animal (or in a laboratory according to research, but through an animal it is the usual thing and what concerns us today in our argument) and that is why studies affirm that it is a zoonosis.
According to the WHO, a zoonosis is an infectious disease that has passed from an animal to humans.
Zoonoses account for a large percentage of all newly identified infectious diseases, as well as many of those already in existence.

How do we treat it?

Many of the diseases we know can be treated through drugs, butwhen we talk about viruses, the most effective way is through immunity, and that’s where vaccines come into play.

So far there are very few vaccines from different laboratories that are administered around the world and some of them are:

Messenger RNA vaccines:

1. Pfizer-BioNTech Tozinameran.
   It is mRNA that encodes the S protein encapsulated in lipid nanoparticles.
2. mRNA-1273 from Moderna.
   It works the same as the previous one.

Inactivated coronavirus vaccines:

1. Sinopharm’s BBIBP-CorV
2. Sinovac Biotech’s CoronaVac
3. WIBP of the Wuhan Institute of BioProducts (Sinopharm) and the Chinese Academy of Sciences.

Viral vector vaccines:

1. Gamaleya’s Sputnik V or better known as the “Russian vaccine”.
   Ad5 and Ad26 adenovirus.
2. AZD1222 of Oxford – AstraZeneca.
   Non-replicative chimpanzee adenovirus that carries the S protein.
3. Ad5-nCoV by CanSino Bio.
   Ad5 adenovirus.
4. Janssen’s Ad26.COV2.S, Johnson & Johnson laboratory.
   Adenovirus Ad26.

Peptide antigen vaccine:

1. EpiVacCorona of the Vektor Institute, which is another Russian laboratory.
2. NVX-CoV2373 de Novavax

But fighting this virus is not only necessary to research to create a vaccine, but also its development, production and finally, the most difficult part, clinical trials and subsequent logistics.

Research and development

Generating a vaccine for the coronavirus involves several challenges, some of which have been achieved with impressive speed, such as the exploration and research stage of the virus.
Normally this stage takes between two to four years, but in the case of COVID-19, only a couple of months were necessary.
Due to the worldwide collaboration between different universities, research groups and private laboratories, it has never been so fast to develop a joint project on a global scale.
CEPI (Coalition for Epidemic Preparedness Innovations) played a leading role in this collaboration.
To understand the pathogenicity and antigenic potential of SARS-CoV-2 and to develop appropriate therapeutic tools, it is essential to profile the complete repertoire of its expressed proteins.
The current map of SARS-CoV-2’s coding capacity is based on computational predictions and is based on homology with other coronaviruses.
As protein complement varies between coronaviruses, especially with regard to the variety of accessory proteins, it is crucial to characterize the specific range of SARS-CoV-2 proteins in an unbiased and open-ended manner.

https://www.nature.com/articles/s41586-020-2739-1

The first thing to be shared was the genomic sequencing of the virus.
The study analyzed 95 SARS-CoV-2 genome-wide sequences that were available at the GenBank, the National Microbiology Data Center (NMDC), and the NGDC Genome Warehouse.

https://www.sciencedirect.com/science/article/pii/S2452014420300960

Second, different variants are investigated to identify natural or synthetic antigens that could help prevent or treat the disease.
These antigens could include virus-like particles, inactivated viruses, or other substances derived from pathogens.

Preclinical stages

Once the vaccine prototype is developed, it must be demonstrated whether the candidate meets a series of requirements in tissue cultures or cell cultures, such as that the vaccine produces the S protein, without mutations, forms oligomers (trimers), is glycosylated, is located in the cell membrane, and that the sequence of the S gene is not altered and remains stable during multiple successive growths and passages.

The next step is to demonstrate the immunogenicity of the vaccine.
This is done in at least two experimental animal models, usually mice or monkeys.
Here it is administered in the form of one or two doses separated by two to four weeks.
During the process, it is compared with control groups.

Within two weeks after the last dose, samples of blood and tissues such as the spleen and lymphoid organs are obtained to analyze serum antibody production and T-cell response, respectively.
For the results obtained to be promising, they must demonstrate that the vaccine produces antibodies against the viral S protein, as well as others directed at the RBD region and other domains of the S protein, and that these antibodies are neutralizing against the virus.
It must also be shown that T cells with the ability to recognize a cell infected by the SARS-CoV-2 virus and destroy it are produced in the lymphoid organs of the animals analyzed.

In the case of adenovirus, mRNA or inactivated virus-based vaccines, the results obtained in mouse and monkey models show that they induce specific immune responses of the Th1 type, with the production of neutralising antibodies, activation of T cells and control of SARS-CoV-2 infection mainly in the lower respiratory tract, with reduced effect on the virus in the upper respiratory tract.

Vaccination begins

To carry out clinical trials in humans , the first step is the production of vaccine manufacturing batches by a company under conditions of good manufacturing practices.
The production of vaccines based on viral vectors uses culture cells, which can be primary or stable, which are infected with the viral vector and after several stages of fractionation, the vaccine is obtained and distributed in vials.

In the case of mRNA vectors, a system of amplification of the virus’s S gene is used, based on a plasmid that contains the S gene under the T7 polymerase promoter and that, when this enzyme is added, produces millions of copies in the form of mRNA that are easily purified.

For those that are DNA-dependent, it starts with a plasmid that is easily purified in bacterial cells such as E. coli.
In the case of inactivated virus, cells sensitive to the virus are infected, then purified and inactivated by physical or chemical methods.
For subunits such as the S protein, this is obtained from the incorporation of the S gene either in eukaryotic cells with release to the supernatant and purification by protein fractionation methods; alternatively, the S protein is obtained from cultures of insect cells infected with a baculovirus that expresses this protein. https://www.ciencia.gob.es/stfls/MICINN/Ministerio/FICHEROS/VACUNAS_GTM_COVID19.pdf

Clinical Trials

The demonstration of an immune response in at least two animal models is an indicator that the vaccine can proceed to the clinical phases.
Here we see that the vaccine induces the production of neutralizing antibodies and activation of T lymphocytes specific to SARS-CoV-2.
It should also be observed that it does not produce adverse effects such as an increase in the infective capacity of the virus in the vaccinated.

The vaccine production process is a long process that requires, according to the European Pharmacopoeia, the validation of the vaccine and the assurance that it is free of undesirable agents so that it can be used in phase I/II/III clinical trials.

Phase I includes a small number (between 20 and 80) healthy people.
Groups of people are usually recruited to demonstrate the safety of the vaccine, including immunogenicity and dose effect.

https://www.sciencedirect.com/science/article/pii/S0952791518300074

During phase II, the number of people is increased to hundreds of healthy volunteers to confirm safety and at the same time determine the induction of immune responses, neutralizing antibodies and activation of T lymphocytes with the ability to recognize and destroy the infected cell.
The trials are randomised and controlled.
If the vaccine does not produce adverse effects and confers immunity with the production of neutralizing antibodies and activation of specific T lymphocytes (CD4+ and CD8+), it continues to the next clinical phase.

Phase III is carried out with thousands of volunteers comparing those who receive the vaccine in relation to those who are administered a placebo, to determine the safety, already in a large population, and their ability to protect against the virus compared to the control group.
In general, Phase III trials are randomized, double-blind and multicenter, so that neither the health workers who administer the vaccine nor the participating volunteers know what they are receiving.

In addition, phase III requires a large number of healthy people in areas with high incidences of coronavirus infection to obtain statistical data that are significant when estimating the efficacy of the vaccine.
This phase is the most critical and where vaccine candidates that are currently being tested can be discarded.

Conclusion

As you have seen, we are in times of great challenges both technologically and humanitarianly.
At the time of writing (mid-February 2021), progress remains unstoppable and can be counted in a matter of hours.
No one knows for sure how or when we will have the pandemic under control and if this will be done or we will have to adapt to living with this virus as we have done with others, such as influenza.
The truth is that never before in the history of humanity has such a huge, ambitious project been developed with benefits for the entire planet.
What we will discover over time will be whether all human beings will have the same access to this historical milestone, but that will be a topic for another article.
See you in the next installment.

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