REASON 3: WE ARE A TEAM, AND WE NEED YOU

British variant B1.1.7

In case the threat of infecting you with COVID-19 still seems trivial to you, the rival is making its moves to improve. In the United Kingdom, a variant of the virus has appeared, named B117, which could be more contagious because it has become a prevalent variant. Its appearance correlates with an increase in infections. Besides, molecularly it presents some changes that would fit with a greater contagion capacity. What changes are these?

The SARS-Cov-2 virus has about 30,000 nucleotides in its RNA genome15. Two-thirds of its genome is used to produce proteins that serve to replicate, together with other proteins in the host cell. The other third of the genome is in charge of synthesising four proteins required for its structure: Protein E (of Envelope), M (of Membrane,) N (of Nucleoprotein), and S (of Spike protein) 16. Of the 29,903 nucleotides of the virus RNA, only 1,273 correspond to the sequence necessary to make Protein S or Spike Protein. When the virus replicates, errors occur and stay in the copies, and, for example, a G nucleotide can become a C. Some of these changes may imply a change of identity in the amino acids that form the protein. The amino acids are 20, and they are also represented by letters (eg, “A” means Alanine). In the case of the British variant, nine changes in nucleotides modify the identity of nine amino acids of the famous Spike protein 17. Variants of the virus have mutations elsewhere, but those affecting the Spike Protein are the most worrisome because this protein is responsible for anchoring itself to human cells.

If any of the Spike Protein mutations improve its anchorage or the entry of the virus into human cells, the virus could be transmitted more efficiently. According to the ECDC (European Center for Disease Control and Prevention) and some publications, of the nine mutations, there are three that could favor better anchorage. These are D614G (mutation whereby amino acid D becomes G), N501Y, and P681H. D614G is an old acquaintance on which there are still discrepancies in whether it would improve the virus’s transmission or not 18. The P681H is next to a critical zone for the entrance of the virus to the cell. Lastly, the N501Y mutation affects a region involved in binding to the ACE2 receptor on human cells, which is the entry gate for the virus. In mouse models, this mutation has been shown to increase virus transmission 19.

The combination of these and other mutations may make the British variant spread better 20. It is pure Darwinian evolution. The mutations that help to survive will stay. If the virus achieves several mutations that, adding their effects, help it to transmit better, those mutations will prevail.

Scheme of the relevant regions in the Spike Protein and the mutations found in the British variant B112.
Upper part: scheme of the 1,273 nucleotides of the virus RNA coding the Spike Protein, and the location of the mutations of the British variant B112.
Bottom left: representation of the SARS-Cov-2 virus. Spike Proteins give a corona-like appearance (hence the name of coronavirus). On the right, Spike Protein with its relevant regions marked in color. The stars indicate the location of the relevant mutations of the British variant.

Thus, among all mutations affecting the 30,000 nucleotides of SARS-Cov-2, the most relevant will be those hitting the 1,273 nucleotides coding for the Spike protein. In this protein key for infection, a critical mutation such as N501Y and other minor mutations could enhance the virus, making it more transmissible and successful. San Marino is a microstate of 34,000 inhabitants and has the worst national team in the world according to the FIFA ranking. San Marino improved when Andy Selva appeared among the 1,000 soccer players in the country. Andy, unlike most of his teammates, became a professional footballer. The Andy Selva “mutation”, which was the most important, coincided with the outbreak of other good players. As a whole, they made a better team that allowed them to win the first and only game in their history in 2004, 1-0 against Liechtenstein, thanks to a goal scored by Andy Selva.

It takes a little longer to confirm with scientific studies that the new British variant is better transmitted and, in that case, to determine how it would affect the R number (or basic reproductive number) of the disease. The variant is not more lethal because the increase in infections has not changed the proportion of those infected in the ICU or those who died. Another question that arises is whether the vaccines developed will be effective against this new variant. The experts and some preliminary assays say that vaccines would work on this variant because the Spike Protein structure does not change that much, and the immune system produces antibodies against different parts of the Spike Protein since it makes (different) polyclonal antibodies. In any case, RNA vaccines are easily adaptable to possible new strains. A variant is different from a strain. To be considered a strain, a variant must have obvious distinct characteristics, not just subtle molecular changes). Another optimistic data supporting the efficacy of the vaccines against the new variant is that previous exposure to coronaviruses very different from SARS-Cov-2, such as those of the common cold, could protect from COVID-19 21.

In any case, the take-home message is that the virus’s evolution is possible and that SARS-Cov-2 also has weapons to improve during its match against Humanity Athletic. Be aware but do not panic.

Vaccine Availability

(Data from Spain, for 48 millions of people, can be proportionally extrapolated to any EU country)

In the first wave of vaccination in Spain, 2.3 million people will be vaccinated with the Pfizer’s vaccine and about 4.2 million with the Moderna’s vaccine. In total, 6.5 million people will be vaccinated with the 13 million doses that the Spanish government has ensured (each person needs two doses) 22.

After thousands of punctures in phase III, and after some adjustments in the doses to be applied, AstraZeneca has announced that its vaccine, based on DNA, reaches efficacy levels similar to those of RNA from Pfizer and Moderna 23, 24. In addition, AstraZeneca’s vaccine has two significant advantages: (i) it is cheaper (€ 2-3 versus € 18-23 for RNA vaccines) and (ii) it does not require as strict a cold chain as RNA vaccines so that the logistics of distribution will be easier (4-5ºC instead of -20ºC for Moderna’s vaccine, or -80ºC for Pfizer’s). Spain has reserved some 31 million doses of the Astrazeneca vaccine for the first half of 2021, which implies another 15.5 million vaccinated. Therefore, 22 million Spaniards, approximately half of the population, would be vaccinated by next summer only with the vaccines already booked.

In addition, the government of Spain has already approved and reserved the purchase of another few million of the Johnson & Johnson vaccines (based on DNA) (20.8 million doses) and CureVac (based on pieces of Spike protein) (23,4 million doses). However, regulatory bodies has not yet approved these vaccines. Another reason to believe that vaccines are good is that countries are fighting and pushing to get them as soon as possible. Obviously, the wealthiest nations will initially have fewer supply problems, and others will have to seek economic and diplomatic formulas to obtain them. That is the case of Argentina, which has not been able to access the RNA vaccines from Pfizer and Moderna, but they have reached an agreement with Russia to receive about 300,000 doses of the Sputnik V vaccine. I do not know the operation details, but if this summer you see Kun Agüero and Messi play for CSKA Moscow, the Russian army’s team, you know the terms of the deal.

Although vaccines are available in some countries sooner than others, they will have to reach everywhere because COVID-19 is a global problem. Considering the globalization and the mobility of people, every nation would be interested in eradicating or controlling COVID-19 in the whole planet. The first million doses of vaccine will help us protect the most vulnerable. Therefore, they will significantly reduce the number of deaths and perhaps the number of patients needing ICUs. Such a reduction will alleviate social pressure and will bring us closer to herd immunity. It is expected that vaccinated people transmit the disease less or not at all, cutting circuits of spread. If this happens, and we increase the pressure on the virus by testing more frequently and quickly, we will lower the R number a lot, and the virus will tend to disappear.

Figure modified from Pollard & Bijker 2020. The effect of a high percentage of the vaccinated population could cut the virus’s transmissibility, reaching what is known as herd immunity.

The match against SARS-Cov-2 is at a critical point. The vaccine will reach you, and you have to help your team, Humanity Athletic. This global team has been making brilliant plays for a long time. The Hungarian Katalin Karikó, after years without research funding, discovered together with the American Drew Weissman that psedudouracils in RNA were compatible with our immune system and that lipid nanoparticles protected RNA from degradation. They sold the patent to the Moderna company, and Karikó was hired by the German company BioNTech, founded by a couple of Turkish researchers. BioNTech developed the initial steps of the Pfizer vaccine. The Chinese quickly sequenced and identified the virus. Therefore, this is a team achievement. China, Germany, Turkey, the United States, Hungary, and all the countries investing in research have provided scientific knowledge to Humanity Athletic for decades. Many individual efforts in basic and clinical research now make sense for a common goal, ending a pandemic.

Remember your teammates who, when we knew little about the virus, did not stop treating patients in hospitals, serving merchandise to supply you, going to investigate the laboratory, charging you at the supermarket checkout. They put their health and that of their families at risk for the good of the team. Then, maybe you didn’t have the opportunity to contribute much to the team’s game, but now you do. Now you can get vaccinated by cutting the rival team’s passing lanes, the sticky and perseverant SARS-Cov-2. Please do it for yourself and the people around you. Please do it for Humanity Athletic, the team of the future. Everyone’s team. Your team.

@raticosdefutbol, @ceronlab

REFERENCES:

17- https://www.ecdc.europa.eu/en/publications-data/threat-assessment-brief-rapid-increase-sars-cov-2-variant-united-kingdom

18- https://www.nature.com/articles/d41586-020-02544-6

19- Gu et al, 2020. Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy. Science  Vol. 369, Issue 6511

20- https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563

21- Ma et al, 2020. Cross-reactivity towards SARS-CoV-2: the potential role of low-pathogenic human coronaviruses. The Lancet. Microbe. Vol. 1, Issue 4, E151.

22- Report from the Spanish Goverment (in spanish)

23- Voysey et al, 2020. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. The Lancet. December 08, 2020

24- https://www.sciencemediacentre.org/expert-reaction-to-the-oxford-astrazeneca-covid-19-vaccine-being-approved-for-use-in-the-uk-by-the-mhra/