The National Health Surveillance Agency (Anvisa) temporarily suspended, on 9/11/2020, phase 3 clinical trials of CoronaVac, due to the occurrence of a serious adverse effect (apparently death of a Brazilian volunteer) that occurred on the 29th. /10/2020. No volunteer will be able to receive CoronaVac while the study is suspended. The Butantan Institute claimed surprise and indignation with Anvisa's decision and reported that the death was not related to the vaccine candidate and demanded that studies be restarted.
Sinovac stated that it trusts the safety of CoronaVac. This type of stoppage should be normal, being part of national and international Good Clinical Practice procedures. We must remember that the vaccine candidates from Oxford (two adverse events) and Johnson & Johnson had previously suspended clinical trials and, after confirming that there was no causal relationship between the vaccine candidate and the observed adverse effect, the clinical trials were resumed . However, last October, a volunteer participating in the clinical trial of the Oxford vaccine candidate died, but Anvisa maintained the studies. Curious!
The National Research Ethics Commission (Conep), linked to the National Health Council (CNS), the entity responsible for analyzing ethical issues in clinical trials, recommended the continuation of phase 3 studies with CoronaVac.
Anvisa needs to clarify this position, as we all expect the agency to act independently, technically, republican, apolitical, without suffering political pressure and interference and to treat all vaccine candidates in the same way. We need to believe in our institutions, that they act with ethics, transparency, honesty and respect. And how sad and regrettable President Bolsonaro’s stance is in celebrating the adverse effect, saying that he “won another one”.
How can anyone celebrate this? Who did you win against? For now, the virus is in control, in a sad 7x1, there are millions of unemployed people and more than 162 thousand deaths from Covid-19. It's impossible not to remember this song by the band rock Brazilian urban Legion, launched in 1987: "What country is this? In the favelas, in the Senate, Dirt everywhere/ Nobody respects the Constitution/ But everyone believes in the future of the nation.”
I have already commented on the issue of the politicization of vaccines in this article e in this one, asking, in this last article, in the topic Oxford vaccine candidate the following: “Imagine if these events had occurred with the Chinese vaccine candidate, what fake news would not be triggered?”. The news of the partial suspension of the phase 3 study with CoronaVac will fuel denialists, the anti-vaccine movement and supporters of the current government. The country of scientific denialism and the personal interests of populist politicians is above the greater health interests of the Brazilian population and is very boring because it is so predictable.
Meanwhile... the flame of hope
Fiocruz informed through its president that the production of the AZD1222 vaccine, in collaboration with the University of Oxford and the British-Swedish pharmaceutical company AstraZeneca, should begin between January and February 2021 and that the immunization of part of the population should begin yet in the first quarter of 2021. Fiocruz expects to produce 210 million doses during 2021, which will be used to immunize 105 million Brazilians (two doses are required). The statement was made during the inauguration of the pyre called “Flame of Hope”, in a homily for All Souls' Day at the Penitência Crematorium and Cemetery, Rio de Janeiro.
In an unusual table between science and religion, the flame signifies trust in science and is expected to be a light to guide scientists' work towards developing a vaccine against Covid-19. The “Flame of Hope” will only be extinguished when a safe and effective vaccine against Covid-19 is discovered. Despite the fact that this time the predicted start date for vaccination was made by a scientist and not by a politician, it does not hurt to remind readers that even with Fiocruz's optimism, the immunization of the population can only begin after approval of the vaccine candidate in phase 3, showing safety and efficacy and no one on this planet can set a date for the start of vaccination. This doesn't all happen overnight.
Fiocruz delivered to the External Committee of the Chamber of Deputies to Combat Covid-19, on 26/10/2020, the Technological Innovation Contract Term signed with the company AstraZeneca. The contract signed on 9/9/2020 concerns the development of the immunizer ChAdOx nCov-19 (AZD1222). AstraZeneca demanded the inclusion of clauses to be exempt from liability in the event of damage caused by AZD1222 in the future, such as serious adverse effects, effects caused by unapproved use of the product, due to only partial effectiveness or even ineffectiveness and possible poisoning. Fiocruz and AstraZeneca will work on acquiring the necessary inputs for production during the term of the contract, until 01/07/2021, the deadline for completing the technology transfer, when Fiocruz will have autonomy for production.
The amount paid per dose was US$3,16 (purchase of 100,4 million doses) and includes the transfer of technology, which should guarantee the national production of over 110 million doses of the vaccine and meet part of the Program's demand National Immunization (PNI). AstraZeneca reported on 01/11/2020 that the Medicines and Healthcare products Regulatory Agency (MHRA) will begin an accelerated review of the vaccine candidate AZD1222.
Another great hope: BNT162b2 in phase 3
“A great day for science and humanity.” Thus, Pfizer and BioNTech informed, through press release on 9/11/2020, that its vaccine candidate (BNT162b2) is approximately 90% effective against Covid-19 after two doses (second dose after three weeks), based on initial data from the phase 3 clinical study. The clinical study involves 43.538 volunteers in six countries, of which 38.955 have already received the second dose by 8/11/2020. Although the initial plan was to carry out a preliminary analysis with 32 or 62 infected volunteers, the companies reached this conclusion after a provisional analysis of the first 94 infected volunteers in the phase 3 clinical study, which leads to the belief that the largest number of infected people ( at least 85) are in the placebo group, which did not receive the vaccine candidate. It seems like a robust response, which shows that vaccines against the new coronavirus, specifically against the spike protein, can indeed work well.
According to the companies, another important result recorded was a higher production of antibodies in volunteers who took BNT162b2 compared to that observed in people recovered from Covid-19. The companies will continue the clinical study until the number of 164 cases of volunteers infected with Covid-19 is reached, hoping that the initial protection rate does not change. It is important to mention that as volunteers were only tested if they showed symptoms of Covid-19, it is not clear whether someone who took BNT162b2 was infected but did not have symptoms.
The data is preliminary and has not yet been published in international scientific journals or reviewed by other scientists. BNT162b2 uses the messenger RNA (mRNA) platform, based on ribonucleic acid, which carries the genetic information of the spike protein, which Sars-CoV-2 uses to invade human cells, with the aim of teaching cells to produce proteins that imitate the external surface of Sars-CoV-2, recognizing it as an invader and preparing an immunological reaction. We do not have any vaccine licensed for human use with this technology. The companies have not observed any serious adverse effects, are awaiting more data on safety and will begin the emergency use process.
mRNA is a fragile, sensitive molecule, it must be protected from exposure to light and heat, and needs to be stored at low temperatures, somewhere around -20 °C or even -80 °C. Distribution in a huge country like Brazil will bring major logistical challenges. These preliminary results are very interesting, important and desirable, but it may still be too early to start any type of vaccination campaign. More time is needed to continue evaluating the safety, effectiveness and for how long this vaccine can protect against infections and severe Covid-19.
BNT162b2 is being tested in Brazil, as are candidates from AstraZeneca/University of Oxford, Johnson & Johnson (USA) and Sinovac Biotech (China). The companies Pfizer and BioNTech expect to produce around 1,3 billion doses of BNT162b2 in 2021. To date, there are no agreements with Brazilian laboratories or institutions to produce the vaccine here, but the federal government is negotiating with companies to purchase BNT162b2, including it in the National Immunization Program of the Ministry of Health. Anvisa, responsible for authorizing clinical studies and approving vaccines for use in Brazil, announced that it has not yet officially received any information about the effectiveness of the vaccine. Let's wait calmly for the publication of the definitive results.
And the effectiveness of Sputnik V also in phase 3?
Shortly after Pfizer and BioNTech's announcement, Russia, through director of a research institute at the Ministry of Health, without mentioning details, also announced that Sputnik V is more than 90% effective against Covid-19. As of 10/11/2020, there is no work published in scientific journals to support this statement. Russia has already requested approval for emergency use of Sputnik V from the World Health Organization (WHO). It is the unbridled race to be the first country to announce a vaccine with proven safety and efficacy against Covid-19.
Research shows drop in adherence to vaccination against Covid-19
Research from the Datafolha Institute released on 7/11/2020 shows a drop in the intention of the population of four Brazilian capitals to adhere to vaccination against Covid-19 and mandatory immunization. The survey involved 1.260 people aged 16 and over in São Paulo, 1.064 in Rio de Janeiro, 868 in Belo Horizonte and 924 in Recife, on November 3 and 4, 2021. The confidence level is 95%, with a margin error of three percentage points plus or minus.
Compared to the previous survey, in São Paulo, Belo Horizonte and Rio de Janeiro, the vaccination adherence rate fell by 7 percentage points, while the percentage of people who refuse to take the vaccine reached an average of 23% in these cities. The average percentage of people who consider that vaccination should be mandatory fell 16 points, from 77% to 61%. China's vaccines suffer greater resistance, even among those interviewed who intend to be vaccinated, being greater among those who approve of President Bolsonaro's government.
We have observed drop in vaccination coverage of our main vaccines in recent years and at this moment it is essential to raise awareness among the Brazilian population through campaigns highlighting the importance of mass vaccination. The National Immunization Program (PNI) is a model for the world, with distribution of more than 300 million doses/year through the Unified Health System (SUS).
A vaccine against Covid-19, regardless of origin and nationality, once approved by Anvisa, must reach everyone through the PNI, be distributed free of charge and cover all age groups. To achieve collective immunity, it is essential to achieve high vaccination coverage with adherence of around 95% of immunization, with homogeneity in coverage, so that adherence is the same in all regions of Brazil.
After all, will a vaccine solve our problem?
Vaccines save more than three million lives a year and we currently have effective and safe vaccines against just over 20 diseases. There are logistical issues involved in mass population immunization strategies, as it is not enough to have a vaccine, it needs to reach those who are going to be vaccinated. It is essential to define a strategy with criteria, ranging from the target audience, the number and frequency of doses and distribution to have the greatest possible reach. The development of vaccine candidates against Covid-19 has been faster than usual for a few reasons. One of them is that some research groups were already investing in new and modern vaccine platforms, another reason is that some teams were investigating vaccines to combat the epidemics of Sars in 2003 and Mers in 2012, caused by other types of coronavirus, but ended not becoming pandemics and were controlled with the adoption of non-pharmacological measures.
Another very important factor was all the learning from the international coalition created in 2017 and which involved governments from several countries to combat the Ebola outbreak in Africa. As it is now a pandemic, affecting the entire planet, another important factor is the enormous amount of financial investment for research, which is unprecedented. The steps are being accelerated, but cannot be skipped. Regulatory agencies in each country are speeding up the evaluation of pre-clinical phases and phases 1 and 2 of clinical trials and must carry out an agile and rapid, although rigorous, assessment of the safety and efficacy results in phase 3.
International standards and regulatory agency rules must be strictly followed. Vaccines will be administered to billions of people and must be safe and effective. Once approved, the vaccine will continue to be evaluated in phase 4, a phase called pharmacovigilance, to continue evaluating safety and how long protection lasts after the doses are administered. Only after the results of the clinical studies, will we be able to define who the priority groups will be.
There is no point speculating that the elderly will be the first to be vaccinated, as we do not yet know whether we will have safe and effective vaccines for this age group, mainly because in practically all clinical trials, the number of volunteers in this age group is small. The first vaccines may not be the best, they may not prevent infection or may not even protect for a long time, but they may reduce the severity of symptoms and the disease.
Vaccination is a collective and not an individual decision
The Federal Supreme Court (STF) should leave a possible judgment on the mandatory vaccination against Covid-19, when vaccines are available. I think that public awareness campaigns, highlighting the importance of vaccination against Covid-19, would be essential at this time. It is very important to publicize and talk to society, so that the population understands the importance of vaccination as a public health tool. The vaccine is a collective decision, not an individual one. Either the entire population is vaccinated or no one will be safe. The Sars-CoV-2 virus does not respect our geographic borders or airspace.
The world is already witnessing the second wave of contamination in Europe
A new stage of movement restrictions and social confinement, to avoid crowded hospitals and more deaths, is taking place in Germany, France, Italy, Poland, the United Kingdom, Spain, Greece, Portugal, Austria and other European countries. It seems that there, as here, the reopening happened too quickly and, last week alone, Europe registered more than 1,7 million new cases of infected people. In the period from 11/10/2020 to 01/11/2020, there was a 150% increase in the number of new cases of Covid-19 in Europe. The number of deaths has also risen by about 32% and hospitals are filling up with the second wave, apparently caused by a variant of the coronavirus, which likely emerged among workers in northeastern Spain in June and has spread across Europe.
Sars-CoV-2 had already undergone an important mutation in amino acid 614 of the spike protein, called D614G, which was previously an aspartate, but is now a glycine, sufficient to confer greater infection capacity. One scientific article, published on 28/10/2020, describes genetic mutations in sequences in the 20A.EU1 cluster, which differ from ancestral sequences at 6 or more positions, including the A222V mutation in the spike protein and A220V in the nucleoprotein.
The new mutation (added to D614G) is also the result of a change in an amino acid, where Alanine 222 is replaced by Valine (mutation 20A.EU1). Viruses do mutate, it is a matter of natural evolution and this new wave may be due to this more infectious, but apparently less pathogenic, variant. These mutations should have no effect on the vaccines being developed, which are based on the original sequence of Sars-CoV-2.
The post-infection
One of the published research in Science magazine, on 28/10/2020, shows that the level of IgG antibodies (immunoglobulin G) in patients who had mild or moderate Covid-19 remain stable for at least 3 months, with a small drop 5 months after infection. This result goes against a previous study published by Imperial College London and elsewhere published study in the journal Nature Medicine on 18/06/2020.
The most recent study in Science analyzed data from 30.082 people who had been examined at the Mount Sinai health complex in New York, in the United States. The authors observed a robust neutralizing antibody response towards the Sars-CoV-2 Spike protein. The Imperial College London study observed 17.576 people with IgG antibodies detected by rapid tests, which are less reliable than the ELISA used in the Science publication.
It is quite normal for the level of antibodies to drop post-infection, but the immune system has a memory response to the virus and can produce new antibodies or a memory response with the production of cytotoxic T cells, which destroy cells infected with the virus. The fact is that we still know very little about the duration of the protective response against Covid-19, especially in the case of reinfection.
In the US government confrontation with scientists is ending
In the US, the president-elect's transition team announced the creation of a task force against Covid-19, launching a website with some of the initial priorities of his management, prioritizing science-based decision making. Other measures to be adopted in the first days of management concern the economic recession, the preservation of the environment and climate change and the fight against systemic racism. The Democrat is expected to announce, as soon as he takes office on 20/01/2021, the return of the USA to the Paris Agreement (on climate change) and the abandonment of leaving the World Health Organization (WHO). It seems, at least there, that the time for the government to confront scientists over the best forms of treatment and prevention of Covid-19 is coming to an end.
Note: This text does not necessarily reflect the opinion of Unicamp.
