According to the survey carried out by the partnership of the consortium of press vehicles formed by G1, O Globo, Extra, Estadão, Folha and UOL, until 08/02/2021, Brazil administered the first dose of Coronavac vaccines (Butantan/Sinovac) and Covishield (Oxford/AstraZeneca/Fiocruz) in 3.816.951 people, or around 1,79% of the Brazilian population and the second dose in 33.723 people. Other data can also be accessed on the website “Our World in Data".As citizens, we have to demand that the federal government take a leading role in ensuring the universality of mass vaccination campaigns.
A vaccination campaign cannot last 16 months, it has to be much shorter and more audacious. The Federal Government needs to provide more doses of vaccines and organize the mass vaccination process. We need a popular outcry, we need the population demanding the purchase of vaccines, pressing for a national campaign to population awareness.
Israel, although it is a psmall and has recently adopted some movement restrictions, vaccinated a third of the population with the Pfizer vaccine and is observing a reduction in the impact of the disease and in the total number of hospitalizations due to Covid-19 in the age group over 60 years old. Israeli scientists attribute the drop in infections and hospitalizations in people over 60 to vaccination and not just current restrictions.
About virus mutations and variants
Mutations in Sars-CoV-2 occur with certain frequency, as the virus is trying to escape the action of the human host's immune system and in a process of natural evolution, the virus may be taking its first steps to escape the protection of the neutralizing antibodies produced. by vaccines. The virus seeks to increase its capacity for multiplication and transmission with the aim of infecting the greatest number of hosts.
Lucky for us, vaccines train the immune system to attack different parts of the virus, a pile of proteins that is a much bigger target than more specific parts that are undergoing mutations and this response depends not only on neutralizing antibodies, but also on cells of memory such as T lymphocytes (T CD4 and T CD8).
Some mutations can make the virus more transmissible, but eventually others can give the virus the ability to evade the immune response. The first time we heard about a significant variant of the virus was D614G, which appeared in Europe and China in February 2020, spread quickly across Europe and the Americas and is now all over the world. This variant binds more easily to the ACE-2 protein (the virus' entry point into our organs) in our cells, compared to the original variant, being slightly more transmissible. But other apparently even more transmissible variants have appeared, facilitated by human behavior.
Let's try to understand a little what some of the terms mean.
What are mutations: They occur frequently and randomly in the genetic material of the virus and do not always make the virus stronger or more transmissible, but some mutations that occur in the Spike (S) protein of Sars-CoV-2 may be more worrying, as this is protein on the outside of the virus, through the receptor binding domain (RDB), which is used to chemically interact with the ACE-2 protein in our organs and enter cells.
Two important mutations occurred in the Spike protein, N501Y, which appeared in 3 variants and E484K, which appears in the South African and Manaus variants. The N501Y mutation exchanged an asparagine (N) amino acid in the genetic material of the Wuhan virus for a tyrosine (Y) residue, which apparently binds more strongly with the ACE-2 protein in our cells, through the receptor binding domain (RDB), with a greater number of hydrogen bonds, while the E484K mutation appears to weaken the action of antibodies.
The N501Y and E484K variants affect exactly the receptor binding domain (RDB), the most crucial region of the most important protein of Sars-CoV-2, Spike (spike or S). However, vaccines can continue to work because they do not just produce antibodies against the receptor binding domain (RDB).
What is a varian: Mchange of the virus in the replication process, so that if a mutation occurs many times, if there is fixation confirmed by genome sequencing, it shows that it is a variant of the original previous virus. Some identified variants are: B.1.1.7 (501Y.V1) in the United Kingdom, B.1.351 in South Africa (501Y.V2) and now P.1. (501Y.V3) In Manaus. The acronyms represent changes in the Spike protein (viral spike). These changes are discreet, but they lead to the dominance of mutant variants over time, as they are able to be more transmitted and dominate the pandemic locally.
The South African and Brazilian variants have mutations in common, occurring at similar points in the virus. A preliminary study published on 07/02/2021 in medrxiv platform shows that the British variant B.1.1.7 is spreading rapidly and could dominate Covid-19 cases in the US in March. According to the WHO, B.1.1.7 is already circulating in 80 countries.
What constitutes a strain: SThey are variants or sets of variants of a given lineage that behave differently from the original virus. Variants that don't behave similarly, like those from the United Kingdom and South Africa, are different strains. We still do not have confirmation whether the Manaus variant is in fact a new strain, if promotes different behavior in the dynamics of the pandemic here in Brazil.
What is Lineage: Cset of variants originating from a common original virus, such as a certain number of mutations that are occurring in several países.
It is still too early to conclude this, we should not yet worry about vaccine escape, which would be the vaccines not working for these virus variants, but the fact is that the more the virus spreads and spreads, the greater the number of mutations that can occur. cause the virus to escape the protective response of both the immune system and vaccines. Therefore, high rapid vaccination coverage is essential in all paises, to prevent the virus from adapting in a process of natural evolution.
It is important to have the largest number of doses of the different vaccines available, organize mass vaccination campaigns as urgently as possible, maintaining the epidemiological surveillance system to quickly identify and detect new mutants.
In this context, it is possible that inactivated virus vaccines may even do better against variants and avoid vaccine escape that may occur with other vaccine platforms. But if it really happens, both messenger RNA (mRNA) and viral vector vaccines using adenoviruses can be adapted to combat mutations.
the variant P.1., with greater transmission capacity, found in Manaus is present in 91% of the samples (from 35 samples, 32 were positive) of viruses sequenced in Amazonas and will soon be found in other regions of the pthere, as the tendency is for it to become dominant. The mutations suffered by this variant of Sars-CoV-2 may have increased its ability to infect people who had already acquired immunity with the first infection.
The fact is that if the virus becomes more transmissible, it doesn't even need to become more lethal, as we will automatically have a greater number of infected people, more serious cases, more hospitalizations and consequently more deaths. If the virus becomes more lethal, it will be more chaotic chaos than the already chaotic chaos installed here. Mass vaccination itself, if not done quickly and continuously, could pressure the virus to mutate to infect people, which could further drive the virus's evolution.
Tests against new variants
A fact that serves as a warning is that a study conducted in South Africa showed that many of the new confirmed cases of Covid-19 were caused by the new South African variant, called B.1.351. Another worrying fact is that around a third of the volunteers had a positive serological result for previous virus infections, which indicates reinfection with the new variant. Apparently, previous immunity acquired after the first infection did not guarantee protection. The E484K mutation, found in the South African and Manaus variants, may be responsible.
CoronaVac: Sinovac announced that it carried out tests that proved, after using antibodies that the body produced after vaccination, that CoronaVac neutralizes the UK Sars-CoV-2 variants (called the "Kent" variant, or B.1.1.7) and South Africa. These results have not yet been published. It is necessary to investigate whether the immunity triggered by the use of the CoronaVac and Oxford/AstraZeneca vaccines is capable of neutralizing the P.1 variant. of Manaus, through the analysis of blood serum from vaccinated people.
Pfizer/BioNTech and Moderna: Pfizer released preliminary results on 19/01/2021 which show that the antibodies produced by your vaccine (BNT162b2) neutralized the Spike protein mutants of the new variants. The Pfizer/BioNTech vaccine managed to immunize people against the B.1.1.7 variant that emerged in the United Kingdom, but the effectiveness dropped a little against the South African variant. This one work was published by Pfizer/BioNTech, now reviewed by other scientists on 08/02/2021 in the magazine Nature Medicine and shows that the vaccine managed to neutralize, in the laboratory, three variants of Sars-CoV-2, from South Africa, the United Kingdom and with mutations that occur in the Brazilian variant.
A Moderna vaccine showed a good immunological response against the B.1.1.7 variant from the United Kingdom, but lost a little efficacy against the B1.351 variant that emerged in South Africa. In both the case of Pfizer and Moderna, researchers used serum from vaccinated individuals in tests against each type of mutation found.
The results showed that the rate of neutralizing antibodies in the blood was reduced by around two to three times when compared to the UK variant and by six to eight times in the case of the South African variant. However, it is important to remember that the Antibodies are just one of the mechanisms of the immune system to defend against the virus, which also relies on memory cells such as T lymphocytes (T CD4 and T CD8).
Novavax and Janssen: Os immunizers from Novavax and Janssen also showed slightly lower efficacy against the South African variant.
Oxford/AstraZeneca vaccine (ChAdOx1 nCoV-19): The vaccine ChAdOx1 nCoV-19 showed good efficacy against the UK variant, according to preliminary research results. On a preprint under review in the magazine The Lancet, scientists reported that levels of neutralizing antibodies (those that eliminate the virus) were lower in vaccinated people who caught the Kent variant, compared to those who caught older variants. But the reduced antibody response was associated with only slightly less protection against symptomatic infections with the Kent variant. Among the small number of people included in the study, vaccine effectiveness fell from an average of 84% against the older variants to 74,6% against the Kent variant.
South Africa announced the suspension of the use of the AstraZeneca vaccine in its immunization program, as preliminary data from a clinical trial showed limited protection against mild illness caused by the 501Y.V2 variant. It is a small phase I and II study, which showed limited efficacy against mild infections due to the South African B.1.351 variant. It was a very small study, with the participation of young people, investigating moderate cases of the disease and it is It is important to highlight that even so, no participant required hospitalization. This is more of a precautionary decision since the study, not yet reviewed by other scientists, did not clarify whether the vaccine is capable of preventing severe forms of Covid-19.
Monoclonal antibodies: Treating the virus with monoclonal antibodies, such as those from the company Eli Lilly, had little effect against the South African variant. Monoclonal antibodies act very specifically against a region of Sars-CoV-2 that is altered by mutations and This could be losing power.
In general, immunizers appear to be slightly less effective against the variant that emerged in South Africa, which has a genetic composition apparently a little more resistant to neutralizing antibodies. If this is proven, one way out would be laboratories work on developing new versions of their vaccines adapted to mutations, updating platforms, like what is done with the flu vaccine, in addition to a possible third dose as a booster to increase the protection of the population.
The solution is to vaccinate, vaccinate, vaccinate en masse, before the virus becomes more virulent.
Anvisa: simplified protocol
Anvisa authorized the new protocol simplifying the process of temporary authorization for emergency use of vaccines against Covid-19. O new guide mentions that the phase 3 study should be "preferably" also conducted in Brazil. However, the request for emergency use of vaccines without phase 3 studies being conducted in Brazil must meet certain criteria:
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Monitoring volunteers to evaluate efficacy and safety for at least 1 year;
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Guarantee of complete access to all study and manufacturing data and informationions generated, as well as guarantee of monitoring;
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Demonstration that pre-clinical and clinical studies followed national and international guidelines.
For more details, click here.
A change in protocol simplifying dthe temporary authorization process for emergency use may facilitate the approval of other immunizers in Brazil. The Ministry of Health announced on 03/02/2021 that it is negotiating the purchase of 30 million doses of the Sputnik V and Covaxin vaccines. Sputnik, which presented 91,6% of Phase 3 efficacy, is developed by the Gamaleya Institute in Russia and has a partnership with União Química in the technology transfer process.
A vaccine candidate Covaxin, produced by the Bharat Biotech laboratory, from inday and based on an inactivated virus platform like CoronaVac, had only phase 1 results published, showing safety and good immunological response. Precis Medicamentos announced on 03/02/2021 that it signed a scientific cooperation agreement with the Instituto Israelita Albert Einstein de Ensino e Pesquisa to carry out phase 3 studies in Brazil. Covaxin is in phase 3 studies in ÍIndia, must be applied in two doses, with an interval of 28 days between them.
Anvisa: provisional measures from the Federal Senate
In a country accustomed to legislating by meditions pprovisional measures, the Federal Senate approved a qwhich affects the temporary authorization for emergency use by Anvisa, so that vaccines that already have authorization for emergency use in paises like EUnited States, European Union, United Kingdom, Russia, China, Japan, Canada, South Korea and Argentina, need to be released in five days in the country. Two provisional measures, MP1.003 and MP1.004, which establish legal and financial conditions, became a bill and if sanctioned by the President of the Republic, they will become Law.
In practice, the vote on the provisional measure authorizes Brazil's entry into the WHO's Covax Facility consortium, with more flexible rules for the provisional authorization of emergency use of vaccines against Covid-19. There is a huge institutional risk associated here, as it should be clear that all regulatory agencies follow the same technical criteria accepted and used internationally.
This decision removes the autonomy of Anvisa, which is responsible for approval, but must grant approval in accordance with the decisions of other international institutes. The Brazilian Congress has previously made mistakes on technical health issues, with the phosphoethanolamine episode, the infamous cancer pill and weight loss medications, and this episode further shows the lack of sovereignty of our institutions in acting for the benefit of the Brazilian population. This violates national sovereignty, as not necessarily vaccines approved in other pare the same ones that come to Brazil or those that will be produced hereOdem not have the same quality.
Inspection of the location and manufacturing method by Anvisa is essential, as is the analysis of the quality of each batch and inputs, which can have an impact on the integrity of the vaccine. Anvisa is responsible for ensuring the safety, quality and efficacy of vaccines after detailed analysis of all data.
Sputnik is a good vaccine, I am in favor of purchasing it, but I am also in favor of an independent and autonomous analysis by Anvisa. I trust Butantan and Fiocruz, but we do not know the production capacity of the company negotiating the production of Sputnik in Brazil. If there are errors in the formulation of the vaccine, this will be taken advantage of by the anti-vaccine movement. Judicialization is coming and Anvisa can go to the STF. What country is this?
Anvisa: authorization of inputs for Coronavac and Covishield
On January 17th, Anvisa approved the emergency use of 6 million doses of CoronaVac (Butantan/Sinovac), in addition to 2 million doses of Covishield (Oxford/Fiocruz), coming from the Serum institute of ÍIndia. These 8 million doses are already being distributed to the Brazilian population. Anvisa also approved, on January 22, the emergency use of another 4.1 million doses of CoronaVac.
Despite the start of vaccination and the distribution of CoronaVac and Covishield across the pTherefore, we still do not have enough doses to immunize even the target population for the first phase of vaccination. In the priority group alone, Brazil has around 15 million people, and we would need around 30 million doses of vaccines. Today we have 10.1 million doses of CoronaVac and 2 million doses of Covishield on Brazilian soil, totaling 12.1 million doses that will be used to vaccinate approximately 6 million Brazilians in the priority group, equivalent to 2.8% of the country's population.
Approval by Anvisa created very positive expectations, but the lack of inputs and vaccines generates frustration and concern. We started vaccinating, it's great, but we can't stop. We are 212 million Brazilians, we need to vaccinate around 2021 million Brazilians in 170, 80% of the population, so we will need 340 million doses. Considering 10% losses, the pthen you need to acquire something around 380 million doses.
According to the signed agreements, both Butantan and Fiocruz received few ready doses. Butantan is expected to receive a total of 46 million doses of CoronaVac from China, with 6 million doses of the vaccine already arriving ready for application, in syringes, and another 4.1 million were filled at the Butantan factory, with 5 mL of vaccine in each vial, each vial with 10 doses, with doses of 0,5 mL. Butantan received the product already formulated, with all the ingredients and excipients. There were no changes or additions. These doses must be used within 8 hoursoras after the vial is opened, to guarantee the quality of the vaccine and avoid losses.
Anvisa approved the bottling process and all quality parameters for batch approval. Thus, new batches can be produced without new approval by the Aagency, following the same protocol. More information you can find at Anvisa website and in the presentations of the 1st. Extraordinary Public Meeting of the Collegiate Board of Anvisa and the 2nd. Extraordinary Public Meeting of the Anvisa Collegiate Board.
New batches of Active Pharmaceutical Ingredient (IFA)
Butantan received on 04/02/2021, a batch of 5.400 liters with inputs (IFA, Active Pharmaceutical Ingredient) which should yield around 8,6 million new doses of CoronaVac after the production stage. Next, the vaccine will be filled, labeled, packaged and subjected to the quality control process. Another batch with 5.600 liters of raw material should arrive by February 10th, allowing the preparation of another 8,7 million doses of the vaccine.
With the two batches, 17,3 million new doses of CoronaVac can be produced, but the exact number of doses will only be known after the production process. The complete process takes 20 days from the arrival of inputs at the factory. Butantan is in the negotiation phase for the release of another 8.000 liters of raw material by the Chinese pharmaceutical company.
And it will be like this until the first 46 million doses are completed. Butantan still has another 54 million doses to receive by September, which should arrive in the form of a few thousand liters of raw material, IFA, the raw material for this immunizer that is imported from China. Butantan is bringing the concentrated vaccine from China and will fill the vaccine at its facilities, transforming 1.000 liters of concentrated IFA into around 1,5 million doses. In this case, as Butantan will carry out the formulation and sterilizing filtration steps, it will be necessary to complete the validation and technical analysis steps and again request temporary authorization for emergency use for approval from Anvisa or request definitive registration of the vaccine.
You know these fruit juices, concentrated syrups that you buy around, like buy a liter, add water to dilute it and prepare something like 5 liters of juice? Concentrated fruit juice is like the IFA in vaccines; without the concentrated passion fruit syrup, you won't make that passion fruit juice, without the concentrated IFA from the vaccines, you won't make the vaccine.
IFA, in the case of Butantan, is the adsorbed active ingredient, fixed on an aluminum hydroxide surface, which also works as an adjuvant, helping to increase the immune response. CoronaVac uses the inactivated, killed Sars-CoV-2 virus. In China, they cultivate the virus in Vero cells, from monkey kidneys, collected there in the 70s and produce millions of viruses. Then they inactivate, or kill, the virus with a chemical called beta-propiolactone. But this substance does not remain in the vaccines, they purify it, only the inactivated virus remains, and then they add the excipients.
In addition to IFA, vaccines may contain sterilized water, salts, small amounts of biological constituents such as proteins, preservatives, stabilizers and antibiotics. to prevent the proliferation of bacteria and provide stability to the active ingredient.
Inputs: Brazil depends on India and China
Brazil depends on India and China to be able to produce the only two vaccines (CoronaVac and Covishield) authorized by Anvisa for emergency use on a temporary basis. AstraZeneca's Covishield vaccine inputs are produced in China and ÍIndia, while the Butantan vaccine is produced in China. This technological dependence on inputs is a structural problem in Brazil and the deficit commercial price in the area today is approximately US$15.
Although Brazil's pharmaceutical industry is among the 10 largest in the world, second Report - International Manufacturer Inspection of active pharmaceutical inputs, published in October 2020 on the Anvisa website, around 95% of the inputs used to produce medicines in Brazil come from abroad. Today Brazil only produces around 5% of the pharmaceutical inputs consumed in the pthere. Most inputs come from China (47%) and ÍIndia (27%), in addition to Italy, Germany, the United States, Switzerland and others paises.
In the years 80, Brazil produced around 50% of inputs, with incentives for multinational and national companies to produce IFA here. Brazil produced antibiotics, which was always considered a matter of national sovereignty, but with the Collor government the market opened up, it became cheaper to import the product and today the pthere it no longer produces any antibiotics, being hostage to technological dependence. Here comes a public health emergency like the pandemic, a situation of serious global health crisis and the result of the technological delay and lack of incentive is that we are left in the queue for inputs and are unable to produce our medicines and vaccines.
It is very difficult to compete with imported IFAs and the input industry in Brazil has drastically reduced investments and today we are dependent on foreign markets. The generic pharmaceutical industry has grown and the fact is that we have few pharmaceutical companies producing inputs. O pthen it did not prioritize a State policy with continuous investments in innovation, with measures to support research for the development of inputs for medicines and vaccines.
Today, with rare exceptions, the national pharmaceutical industry does little innovation, has a family character and relies on a comfort zone, investing in copies of products developed by companies abroad. If we want to actively participate in the innovation process, there needs to be a change in the mentality of the Brazilian pharmaceutical industry.
See the importance of investing in science. The lack of investment in science is the main reason for Brazil's dependence on inputs for medicines and vaccines. Science has provided an extraordinary response and today we have several vaccine options to combat Covid-19. We need vaccines, or we will have even more complicated days ahead. Every day that passes without vaccines will result in thousands of people becoming infected and, unfortunately, more deaths in the future, which could have been prevented by vaccines.
We are also fighting the anti-vaccine movement, a cruel and irresponsible movement that fights vaccines, but does not propose alternatives to combat the pandemic. But if we don't have vaccines for the entire Brazilian population, they win by WO and the pThen you will continue burying your dead without even being able to say goodbye. Brazil deserves more, deserves better luck.
While millions of doses of real vaccines are yet to arrive, the best vaccine at the moment is to maintain non-pharmacological measures, such as wearing a mask, physical distancing and hygiene habits. And even with the start of the mass vaccination campaign, we will need to maintain the use of masks and physical distancing for some time, until we are all safe. And we need vaccines to be distributed to everyone in an equitable and egalitarian way.
VACCINE UPDATE
Astrazeneca/Oxford: general efficacy of 82%
New phase 3 efficacy data for the vaccine ChAdOx1 nCoV-19 (Covishield) published in the form of preprint (still unreviewed by other scientists) na magazine The Lancet, show an overall efficacy of 82,4% after two doses with a three-month interval between doses. Vaccine efficacy is greater at longer intervals and a single dose of the vaccine is 76% effective in the period 22 to 90 days after vaccination. The vaccine showed 100% efficacy for more serious cases of Covid-19, avoiding hospital admissions and has the potential to reduce transmission of the virus, based on the 67,6% reduction in viral load in volunteers after the first dose.
The study involved 17.177 volunteers in three studies (United Kingdom, Brazil and South Africa), with 8.597 taking the vaccine and 8.580 taking a placebo. Fiocruz filed a request for definitive registration of its vaccine with Anvisa. If approved, the authorization will allow the vaccine to be used across the entire Brazilian population.
CoronaVac: know what its composition is
According to bubble from CoronaVac, the composition of the vaccine is as follows: each 0,5 mL dose of injectable suspension contains 600 SU of the inactivated SARSCoV-2 virus antigen, plus the excipients: aluminum hydroxide, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride sodium, water for injections and sodium hydroxide for pH adjustment. CoronaVac does not contain preservatives, according to the leaflet.
This is a fundamental step in making the vaccine available to Brazilians in record time. Butantan's technology and expertise will allow the production process to be carried out in the factory itself, but requires certification from Anvisa. From then on, Butantan will be able to carry out the complete transfer of technology and produce the IFA nationally, producing the vaccine fully. Then yes, Brazil will have autonomy in the production of this vaccine and we will become independent.
As soon as the new inputs arrive from China, Butantan's expectation is to be able to double vaccine production, going from 1 million to 2 million daily doses of the vaccine. I hope that Butantan will have the capacity for full production autonomy in the first half of the year, but there are a series of steps that must be done correctly for this to happen. Today, Butantan has the capacity to formulate the API, filling, quality control, labeling, packaging, but it needs to produce the raw material, which is the active pharmaceutical ingredient.
ChAdOx1 (Covishield): what is it made of
The Oxford/AstraZeneca ChAdOx1 vaccine uses a chimpanzee adenovirus as a platform. Second the leaflet caof the vial contains 10 doses and each 0,5 mL dose contains 5 × 1010 viral particles (pv) of replication-deficient, recombinant chimpanzee adenovirus vector (ChAdOx1). The vaccine contains excipients such as L-Histidine, L-histidine hydrochloride monohydrate, magnesium chloride hexahydrate, polysorbate 80, ethanol, sucrose, sodium chloride, disodium edetate dihydrate (EDTA) and water for injections.
Fiocruz expects to deliver around 210,4 million doses of ChAdOx1 from the IFA by the end of 2021, with 100,4 million doses by July 2021. With the complete transfer of technology, Fiocruz will begin production in Brazil It is IFA import will no longer be necessary, ensuring autonomy in the vaccine production process.
The Ministry of Health reported that it received on 06/02/2021, a batch with around 90 liters of IFA for the Covishield vaccine, stored at -55 degrees Celsius. The raw material for preparing the immunizer was manufactured in the Wuxi Biologics laboratory, in Shanghai, China.
O Institute of Technology in Immunobiologicals (Bio-Manguinhos/Fiocruz) will carry out the IFA thawing steps, formulation with dilution and addition of other components to ensure the maintenance of the properties of the vaccine and allow it to be stored for 2 to 8 degrees Celsius and prepare around 2,8 million doses, which after filling, labeling, packaging, quality control and approval by Anvisa, can be distributed to the population. Fiocruz has all the industrial details to guarantee the correct formulation of the vaccine and expects to receive three more batches of IFA in February to produce another 15 million doses.
