Archive for September, 2020

Understanding SARS-CoV-2 and COVID19

Monday, September 14th, 2020
Image Source: Ann Kiernan for “The Washington Post”, June 18, 2020

Here we go: another blog post on the coronavirus pandemia that is ongoing globally. The race to a vaccine continues (will discuss a little about that below), however this post will be focused on the virus that caused the disease COVID19 (Coronavirus Disease 2019), named SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), its biology, complexity, how changes in its genetic material could make harder to develop vaccines against it, the latest reports on tropism to specific human cells and organs and how the outlook for the near future looks like. In addition, I will discuss cases being reported of secondary infections in the same person and people that was “cured” from a first infection developing complex syndromes (especially children) and long-term neurological problems in older people. This pandemia is ongoing for more than 6 months, and I am very happy with how the scientific community is collaborating worldwide (collaboration in science is key, totally opposite to the system we were used to before) accelerating our understanding on the invisible enemy we are dealing with. Unfortunately, it is still not enough to eliminate it yet, but we are on the right track.

Biology of the Virus

What is the best way to understand a virus and its biology? First, we need to isolate the virus from patients and sequence its genetic material. With this information, we can use the databases available to scientists to compare its sequence and even identify how it is evolving comparing different strains in different places of the globe. The second thing to do is to study how the virus “attacks” the host (yes, us, humans). The good news are that both information is getting out fast with several scientists studying both topics very deeply. There is already a catalogue of SARS-CoV-2 mutations available and comparisons to see which genetic changes facilitate the infection and how it will affect the disease course (for more information check the article describing it here). To date, more than 100,000 isolates have been sequenced and made public ( Two SARS-CoV-2 viruses collected from anywhere in the world differ by an average of just 10 genetic letters out of 30,000 (the virus genome has 30 Kilobases or 30,000 bases) that could confer evolutionary advantages. Based on these studies, it is a possibility that the virus will acquire mutations that could change its susceptibility to antibodies and immunity affecting treatment and vaccination. The second way to understand the disease is to analyze the the tropism of the virus when it enters the human body. Tropism is which cells it binds to and in which organs it affects when inside the body. A recent report just released from a group that evaluated thousands of cell types (a type of “coronavirus cell atlas”) and organs from patients infected identified that the virus enters our respiratory system, however it has tropism to several other cell types and organs – see the Figure below. The idea here is that all these cell types in different organs in the human body have a protein (lock) that binds to the virus “spike” protein (key). When the key unlocks that lock the virus enters the cell and multiply, killing it and causing all the signs and symptoms that we see in the disease. Based on this study, we can tell how complex is the spread of the virus in the human body and why each person has a different reaction to the disease.

Source: Figure from article entitled “A single-cell RNA expression map of human coronavirus entry factors” published in the journal “Cell Reports”

Re-infection Cases

Another problem that worries the research community, especially for a successful vaccine to work, is the recent reports of cases of re-infection with the virus. Most of these are probably re-infection with other strains, very similar to the common cold or flu virus that we can get it more than once in a year, for example. The first report was in Hong Kong (see article here) and now we see a lot of reports with cases of re-infection. Most people who are infected with the coronavirus produce detectable antibodies that would be expected to protect against a second infection by the virus. Even people who had only mild symptoms may also have immune “memory” that prevent symptoms on a second exposure. It is clear now that is not the case. Even though it is early to make conclusions, this could impact vaccination when a vaccine is ready.

Post-COVID19 Syndrome

The last important issue that have been reported since April of this year when the spread of the virus started and now it is much clearer is that people considered cured developed neurological problems and other signs and symptoms that persist until today. Remember (check the Figure above) that the virus infects cells from the brain and the nervous system, so neurological problems would be expected. For the sickest patients, infection with the new coronavirus is proving to be a full-body assault, causing damage well beyond the lungs. And even after patients who become severely ill have recovered and cleared the virus, physicians have begun seeing evidence of the infection’s lingering effects (check the article for more information here). Another worrying post-coronavirus effect that has been reported is a mysterious, new disease called multisystem inflammatory syndrome in children (MIS-C, and also known as pediatric multisystem inflammatory syndrome or PIMS). It has affected hundreds of children around the world since it was first discovered earlier this year. Other syndromes have been reported everywhere now and that is concerning. What is causing these post-COVID19 syndromes? Why in children? We still do not have the answers to these questions. Let’s hope the scientists can uncover this mystery.

Updates on the Vaccine Race

Finally, let me discuss a bit about the “pause” that the AstraZeneca/Oxford University vaccine had last week because of a severe side-effect in one patient that had inflammation in the central nervous system. First, that is common to happen, especially when you are dealing with a fast-track vaccine trials and with people with different genetic backgrounds. Second, the “pause” was important to show to the world that this vaccine is trustworthy since the researchers from both places coordinating it are using the best scientific guidelines with very strict rules (trust is important!). Third, side-effects will happen, the severity of them that will be key for a successful vaccine. Finally, the vaccine race continues and I just read that AstraZeneca and the University of Oxford is going forward with their trial after the “pause”.

Final remarks

All the information I just discussed here is just the tip of the iceberg on the complexity of this virus and how it infects humans. We are starting to understand several processes on how the virus infects human cells, which cells and organs have the tropism for it and how people with different genetic backgrounds from different places react to it. Post-COVID19 effects are getting clear (it happens) but we still have lots of WHYs to focus on right now. I always finalize my posts with some advices: the best thing to do now is still social isolation, take the measures to avoid getting infected and stay mentally sane. I confess that I am already having mental issues (don’t leave the house for almost 4 months!). Stay strong. We will overcome this crazy pandemia. And let’s thank the scientists and healthcare professionals everywhere that are making it possible to gather all the information we have to date on this disease. A brighter future is closer… I hope!

Coronavirus Pandemia and the Vaccine Race

Tuesday, September 1st, 2020

This blog post will be focused on the race for a coronavirus vaccine that is happening globally. My main objectives here will be to explain in a general way how a vaccine works, to give some examples of successful ones, and the difficulty to develop specific vaccines for viruses. In addition, I will discuss some of the vaccines in the last clinical phases for the coronavirus and last, but not least, how it will get to you, me and to all global citizens when it is ready; this is the most complicated part. Just as a reminder today, September 1st, we have at least 850,000+ deaths and 25.5+ Million people infected by the coronavirus globally (data from the “Johns Hopkins University COVID19 Global Tracker”). We really need a vaccine to decrease the spread of this virus otherwise things will definitely get worse. Vaccines typically require years of research and testing before reaching the clinic, but scientists are racing to produce a safe and effective coronavirus vaccine by probably the beginning of next year (best estimate). To date, the number of vaccines under development worldwide are in the hundreds, however I will focus here on the ones that are in later stages in clinical trials with more possibilities of being successful. Researchers are testing 36 vaccines in clinical trials on humans, and at least 89 pre-clinical vaccines are under active investigation in animals (to see more information check “The NY Times COVID19 Vaccine Tracker” updated daily).

Types of Vaccines

Vaccines consist of five specific types: live attenuated microbial particles, inactivated microbes (by heat or any other methods), toxoid vaccines (part of the virus or bacteria that cause an immune response and immunological “memory”), conjugated or hybrid (most of it will be a non-pathogenic virus/bacteria with parts of it as targets) and new technologies such as nucleic acids (DNA & RNA) vaccines (for more information on vaccine types check this article). One example of a vaccine that used the attenuated virus is the polio vaccine that was able to almost eradicate the disease from the world (eradication just happened in Africa this week thanks to a lot of efforts from the WHO and its partners, but we still have isolated cases – check the article here).

Viruses and The Challenges Ahead

There are two types of viruses: DNA and RNA ones. They differ in the way they use our cells to produce more viral particles. The trickier ones are the RNA viruses since they use the cell machinery in a more successful way to “reproduce” and kill cells. For instance, the HIV virus is an RNA virus and until today researchers were not able to develop a vaccine mainly because HIV infects directly our immune cells, the ones that should “remember” and kill them in a second infection. For viruses causing infection in the respiratory tract such as the common flu, the H1N1 and now the SARS-CoV-2 it is not easy to develop vaccines. These viruses mutate a lot and the way our immune system “attacks” viruses can be different from other pathogens such a bacteria, for example. Additionally, each person has a different genetic background, thus different immune responses. This is why we are in this situation right now.

Vaccines Under Development

Let’s discuss some of the vaccines that probably will come first in the race and how they work: the AstraZeneca in collaboration with the University of Oxford in the United Kingdom (UK) and the Moderna Therapeutics in the United States of America. These are among the handful in Phase 3 clinical trials. Others include vaccines by Merck, the University of Queensland, GSK, Pfizer, Sinovac, Casino Biologics – the Chinese vaccine that was just reported, amongst others. Well, the AstraZeneca/Oxford and the Chinese Vaccine (their clinical study was just published on the well-respected journal The Lancet) use an adeno-associated virus genetically engineered as a “Trojan Horse” with an immunogenic protein (or an immunogenic part) of the Coronavirus (COVID19). It is difficult to explain right, but genetically engineered viruses have been used in research and clinical laboratories for research for decades. The idea here is that our immune system will fight “lightly” this foreigner hybrid virus and “create” a memory against it. The “secret sauce” for a vaccine efficacy and efficiency that we still do not know for the coronavirus is how long this immunological memory will last. For the polio virus one shot can last almost our whole lives, for the common flu and H1N1 we need to take it every year and probably from what I am reading about the coronavirus, we will need several shots during a single year based on the reports showing that the immunological “memory” doesn’t last too long. The Moderna vaccine uses a different approach based in nucleic acids. An RNA vaccine uses viral genetic material (in this case the coronavirus RNA) to produce antigens that would allow the body to learn to respond in a second infection by it. This is the first of this kind, that is why there is a lot of skepticism and concern. The last one that I wanted to write about is the “russian” vaccine that the media is discussing a lot recently. For me, as a scientist, if there is no data, no publication, no clinical trials and no information available I do not trust. The russians did not disclose anything: how the vaccine was developed, how it works, the tests that were done, if it is safe enough or not, etc.* To finalize, the most problematic part after all clinical and toxicological tests are cleared and the vaccine is ready is to produce it in large scale and distribute it globally.

What The Future Holds?

Several questions are still open to discussion based on the clinical scientific facts we have until now: Which country will get it first? How much a dose will cost per person? How many immunizations we will need to be safe and start walking around going back to normality? How the governments will deal with the bureaucracy to buy and distribute it to its citizens? We never had in my lifetime something involving so much money and interests in healthcare in a global scale like this. A lot of people can get filthy rich with the outcome of a successful vaccine, that is for sure. Thus, what the future holds in this race? Who will win? And, most importantly, when the first vaccine is approved what will be its immunological efficacy? 50%? 60%? Meaning that some people will not get the expected immune “memory”. Other factors that should be taken seriously are side effects of the vaccine (for example, in the Chinese vaccine study more than 90% of the group that received it had at least one side effect). Well, we are just watching this race and rooting for a good winner. I hope we will have something until the end of this year, and that it could reach every single person in the globe. A little utopic to think like this but we need to be positive. To close this post we still have an open question: Who will be the winner? What do you think?

*Footnote: An article describing a non-randomized phase I/II clinical study from Russia was published today, September 4th, with 76 people after my post was published. The strategy used was based on an engineered adeno-associated virus with an immunogenic protein from SARS-CoV-2. Even with a very low number of participants, the study is encouraging; however as stated in the Conclusions, the authors make it clear that further clinical investigation will be needed to test effectiveness. To check the full article in the journal “The Lancet” click here.

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