It was in 1984 that she took her first steps in teaching, as a junior teacher assistant at the Faculty of Medicine of the University of Lisbon.
Today, in 2021, she is an Associate Professor with Aggregation at the Laboratory of Clinical Pharmacology and Therapeutics of the Faculty of Medicine, and although she has made a “pause” in teaching, she is proud of “the connection to the Faculty”, as she mentioned in the last FMUL Talk.
Currently, she is Chief Medical Officer at the CHDI Foundation (private foundation dedicated to researching therapies for Huntington's disease) in Princeton, United States.
An indispensable individual in medicine and pharmacology in our faculty, she worked at the Medicines Agency as an expert.
We are talking about Ana Cristina de Brito Almeida Sampaio Cruz, or, for us, just Cristina Sampaio!
The news@FMUL asked the Professor to tell us about vaccines to combat Covid-19, which has generated so much controversy, in order to demystify the issue!
Has the promise of the end of the storm finally arrived with the discovery of the vaccine?
Cristina Sampaio: The beginning of the end of the storm will only come when vaccines (plural) are effectively available and administered to a large majority of the population, not only in the country, but in the world. The existence of vaccines as abstract entities that exist somewhere gives some intellectual comfort, but does not change anything on the ground.
What will the real benefit be?
Cristina Sampaio: The "real" benefit cannot be quantified yet. We know that in the context of clinical trials, the various vaccines tested are highly effective, above 70%, even reaching 90-95%, in reducing cases of disease. That is why the benefit we can expect, when a significant fraction of the population is vaccinated, is a visible reduction in cases of disease and, consequently, a reduction in the infection health risk. By reducing the risk of illness to residual values, vaccination will allow economic activities to resume and will enable relaunching social and cultural life. There are still many uncertainties, some directly related to the effectiveness of vaccines, i.e., will we have an efficiency close to 90%? How long will immunity last? Will it be necessary to update vaccines periodically? Will vaccination be effective to protect against infections (without disease) and consequently stop transmission? This last question is extremely important, although most people think that they don’t mind being infected if there are no consequences. However, it will be a problem if the virus continues to circulate without restraint because as it goes through hosts, it will mutate, the more it transmits itself the more mutations it will undergo, which can lead to vaccine-resistant variants. In fact, this is one of the open questions, what will be the evolution of the virus in the face of the pressure caused by a vaccinated population. In conclusion, the immediate benefit of extensive vaccination is the creation of space to reduce individual risk, relaunch the economy, and rethink the organization and sustainability of health services. The big health gains are going to be associated with this economic recovery, and the reorganization of the health system.
We must not forget that vaccination will only be effective if logistical problems are resolved. Just as COVID-19 bears little resemblance to influenza, vaccination for SARS-CoV-2 also appears to be much more complex than influenza because it has to cover the entire population, rather than focusing on groups of greater risk, and has to be worldwide coverage. If there is the need to repeat the administration every year, it will be a huge problem. Just remember that the WHO makes a huge effort to vaccinate children in low-income countries, with vaccines that are effective for life, such as measles, and are far from reaching everyone who needs them.
Many people fear the vaccine considering that everything came up in a short time. Can you demystify this issue?
Cristina Sampaio: One can be completely confident that there was nothing mysterious, nor stages skipped. Nothing in life is zero risk! Vaccines for Covid-19 are safe, and unlike all other vaccines and drugs about which safety information slowly accumulates over years, the pandemic situation meant that in a few weeks there would be information on millions of vaccinated persons. Therefore, we can be confident that the rate of serious adverse reactions is extremely low.
Two very positive things happened that led to the successful development of vaccines in a short space of time:
1) scientists were fully prepared for this challenge and the technology to produce the vaccines had already been developed, and could be quickly adapted to the SARS-CoV-2 problem;
2) all global partners have aligned themselves on a common goal: to develop and produce these vaccines. Non-refundable financial investment has reached unprecedented proportions (we must not forget that clinical developments in drugs and vaccines cost many millions of euros, and part of the time is spent looking for investments); and international collaboration, which included ordinary citizens who volunteered to participate in clinical trials, and regulatory authorities were very generous and had enormous scope. This expression of global goodwill will go down in history as an example of the good humanity can achieve when it comes together in a common goal.
I think that in March we were all sceptical about this level of collaboration, and we thought it was better to warn people that developing a vaccine in one year would be a miracle. All of us, who spent our lives designing, coordinating and evaluating clinical trials, could only see the difficulties and not the opportunity. To put it in context, sometimes just approving a contract for a clinical trial can take 3 months or even longer.
There is an important point to consider, the development of vaccines is technically easier than that of drugs, and in the context of a pandemic, there is no shortage of patients to carry out clinical trials. It should be noted that vaccine development is often conditioned because there are not enough cases to complete clinical trials. Of course, there are difficult cases such as HIV and malaria, but the success rate of vaccine development is on average 40%, while that of medicines is around 16%. It is a very significant difference.
There are guidelines produced by the EMA (European Medicines Agency) and the FDA (Food and Drug Administration) for the development of vaccines. These guidelines predate the pandemic, the latest version dates from 2018, and define what the requirements are in terms of quality, effectiveness and safety for any vaccine. I must say that I compared the requirements in these guidelines with the vaccine development programmes that have already been approved and I can assure you that all requirements, mandatory before the pandemic, have been met.
Why is it that in the case of Covid-19, the vaccine have a higher success rate than drugs?
Cristina Sampaio: As I said in the previous answer, vaccines in general, not just Covid-19 vaccines, have a much higher success rate than drugs. Vaccines have a great advantage over drugs, the agent causing the disease is known, well characterized and clearly the "culprit". Vaccine developers have to create a process to introduce this agent in our immune system; it is not an easy task, but it is a well-defined task. In the case of drugs, the main problem is to find out which is the "agent", i.e., the target. Diseases are complex changes in one or more systems, it is difficult to find out what the primary changes are and what their relative importance is. To know what the target of a new drug should be, we have to demonstrate that that target is truly a cause, or a factor in the development of the disease. Many drugs are developed based on targets that have not been sufficiently validated, or have been developed in animal models that do not have sufficient correspondence in humans. This is one of the main reasons why the drug development success rate is so low.
After the meeting that took place at Infarmed, in the middle of January, and where countless experts were heard, one of the numbers presented foresees that in a few weeks the number of infected people may double from 10,000 to 20,000 cases, and that the number of dead will remain at an average of 150, even if going into lockdown. Until we can vaccinate as many people as possible, will we lose many lives? Is there a way to speed up the process?
Cristina Sampaio: To speed up the vaccination process, two things are needed: 1) to obtain many more doses of vaccines; 2) to speed up the distribution process. Right now, the major limitation is access to more doses of vaccines. Vaccine production chains are being pushed to the limit. All rich countries are putting enormous pressure on getting more doses. Portugal has no bargaining power, with the exception of what results from being a member of the European Union, which is a huge advantage, but insufficient. Thanks to the European Union, we can guarantee that we will receive enough doses to cover the population, but what is missing is the rapid acquisition of these doses. This problem affects the European countries in a reasonably similar way. Companies are doing their best to increase production, but it is not easy because raw materials have limited availability.
What is an RNA Vaccine (to which the Professor refers in the FMUL Talk of 7 January)?
Cristina Sampaio: RNA is a nucleic acid like DNA; DNA is the basis of our genetic code, it resides in the cell nucleus, where it is relatively protected; as it is separated from the compartment where most of the action at cell level occurs through the nuclear membrane, it needs a messenger. This messenger is RNA. Thus, the RNA makes copies of the messages contained in the DNA and passes it to the cytoplasm through the pores in the nuclear membrane. In the cytoplasm, these copies, in the form of RNA, are used to make proteins. This molecular machinery is continuously in operation in our cells. What vaccines do is to take advantage of the existing machinery (in a similar way that the virus also does). RNA vaccines use RNA to carry the protein message that we must synthesize into our body in order to stimulate our immune system to produce the necessary antibodies. There are other technologies that achieve the same result, but RNA is easy to synthesize and easy to change if vaccines need to be adapted to future mutations.
If it was possible to speed up the discovery of the vaccination process based on RNA, why haven't vaccines against cancer, which are studied precisely using the same molecule, not yet been discovered?
Cristina Sampaio: "Cancer" is an abstraction, there are hundreds of oncological diseases that are very different from each other and that is why it can never be generalized. In addition, RNA vaccines for cancer are treatments and are not for prevention. There has been significant progress with RNA vaccines in some cancers. The point is that even within the same cancer disease, each patient has genetically different tumours, so it is not possible to create vaccines for a specific disease, they have to be created for each tumour individually. "The development of this technology is underway, very likely to be successful and will have its place in the panoply of cancer treatments, but it cannot be seen as a solution to eradicate "cancer", which is a myth. The issue with RNA vaccines in the context of cancer diseases, as I said above, is finding the right targets to create the appropriate RNA. In the case of the COVID-19 vaccines, it was perfectly clear that the target was the spike protein of the virus.
How do we explain that we have vaccines that need two doses to be more than 90% effective and another vaccine that only requires one dose?
Cristina Sampaio: All currently approved vaccines are two-dose ones. The Janssen vaccine (Johnson and Johnson), which is still being developed, tested two administration forms: just one dose or two doses. It appears (data not yet published) that one dose may be sufficient. The rationale for the two doses is based on a paradigm according to which the first dose stimulates the immune system, as if waking it up, but for that initial stimulus to consolidate a second dose will be required.
There is always some efficacy with just one dose, but to increase that efficacy, the second is necessary. To try a single dose procedure, it is necessary that the stimulus caused by that single dose is sufficiently intense; the intensity of the stimulus can be related to the amount of the target protein that is produced and also to the duration of that production in our body. The RNA of the Pfizer and Moderna vaccines is destroyed very quickly and therefore the amount of protein produced will be small, while the Janssen vaccine is a DNA vaccine and may have a longer durability with the consequent greater production of the target protein. These differences will have to be specifically studied to be able to be understood.
It became known this week that Janssen Pharmaceutical also completed the 1st and 2nd phase of clinical tests. Do you think that another “front to fight this disease” may be available soon?
Cristina Sampaio: Yes, surely, in order to vaccinate our 10 million Portuguese and to vaccinate the rest of the world, many vaccines will be needed, and vaccines that use different raw materials because part of the limitations on production is the lack of raw materials.
What does a doctor feel when he has to choose between lives?
Cristina Sampaio: Doctors, like all human beings, are not monolithic beings. Reactions to situations of great cognitive and emotional dissonance, such as having to choose who to treat and who to leave behind, will certainly be different but always painful and traumatic.
I vividly remember in March last year when Italy faced the outbreak of COVID-19 in Dantesque conditions, and the Italian college of Anaesthesia, Analgesia, Resuscitation and Intensive Care published guidelines to guide access to intensive care, which was no longer available to everyone. Reading them in Italian (which I do not master, I read it because it is similar to Portuguese) caused me great anguish, and gave me the feeling that we had crossed a moral border. I must say that under the circumstances, I consider these and other similar guidelines to be absolutely necessary.
Cristina Bastos
Editorial Team
