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Since the beginning of our COVID-19 discussions in the early weeks of this calendar year, we have touched on various aspects of the biology of SARS-CoV2 (the virus that causes COVID-19), its pathophysiology (the way that it causes disease in those who become infected), treatments, and the quest for vaccines. Currently more than 60 million cases have occurred worldwide, the number of deaths globally is approaching 1.5 million, and the numbers rising sharply in the United State, but there is some light visible at the end of the tunnel. Recently, we discussed encouraging results from clinical testing of COVID-19 vaccines produced by Pfizer and BioNTech and by Moderna, vaccines consisting of molecule of what’s called mRNA, delivered to body cells within a spherical container built of fatty substances. Rather than reaching the public through scientific papers published in peer-reviewed journals, the news on Pfizer-BioNTech and Moderna vaccines reached us through press releases and the same is true of news of another COVID-19 vaccine, this one from the AstraZeneca company, working with scientists at Oxford University in the UK.
The various vaccines that look promising to be effective and available to massive amounts of people in the upcoming year are all in phases of clinical testing known as phase 2 and phase 3. Sometimes overlapped or conducted in the same study, phases 2 and 3 focus on determining how effective a vaccine is at doing what is designed to do —either stopping a disease from spreading or at least preventing or reducing symptoms in those who do become infected. This is in contrast with phase 1, in which only the safety of a vaccine is studied (although safety continues to be studied throughout phases 2 and 3). Whereas the reports from Pfizer-BioNTech and Moderna leave us uncertain as to whether their vaccines merely prevent infected people from developing COVID-19 symptoms or also prevent infected people from spreading the virus to others, the good news about the AstraZeneca-Oxford vaccine is that it does indeed appear to be effective in preventing infection of others.
One thing that may frustrate you as a mother-to-be is that, like most vaccine trials, the clinical trials of the handful of vaccines that have been developed for COVID-19 have not been including pregnant women among test subjects. This is despite the fact that there have been proposals to include pregnant women at least in phase 3 testing, not only to verify that the vaccines are safe specifically in pregnancy settings, but also to determine if the findings on vaccine effectiveness in non-pregnant volunteers applies to pregnant women, or if the dosage (how much vaccine in each shot) or the timing of shots (amount of time between shots) needs to be tweaked for pregnant women.
Generally, what has happened in the history of vaccines is that evaluation of a vaccine in pregnancy is carried out more informally and after the vaccine has already been approved for massive use. Probably, something like this will happen with the COVID-19 vaccines; vaccination will be recommended for pregnant women based on more than a century of experience suggesting that only live vaccines —vaccines in the form of an infectious agent that has been weakened in its ability to cause disease or that causes non-lethal disease, but is still infectious in that it will multiply in body cells— present any serious danger to an embryo or fetus. In the case of the COVID-19 vaccines, we are talking about strategies that are very high-tech compared with the old strategy of taking the actual disease-causing agent and changing it in a way to weaken it. Instead, the various COVID-19 vaccines all involve selected molecules that the SARS-CoV2 virus has on its surface like a coat and getting those molecules produced on the surface of something else. This enables your immune system to learn to recognize it, without your body ever being in danger of developing COVID-19 disease while the immune system goes through the learning process. With most of the promising COVID-19 vaccines, the surface molecule that we’re talking about is the notorious spike protein, the molecule that gives the virus its crown-like, or corona, appearance when viewed with electron microscopy and also that enables the virus to enter your cells by attaching to a protein called ACE-2 that is naturally present on the surface of many types of body cells.
Whereas the business end of the Pfizer-BioNTech and Moderna vaccines is a molecule of mRNA that carries the recipe for building the spike protein, the recipe for the spike protein in the AstraZeneca-Oxford vaccine is a molecule of DNA. You may know that DNA is the molecule that stores your genes. DNA and RNA are very similar, but DNA is the more famous chemical. Most of your body cells have a nucleus, which contains chromosomes, each of which is a long strand of DNA that includes many genes, each of which is a sequence of DNA building blocks. In a process called transcription, the sequence of a gene is used to build a molecule of a kind of RNA, called mRNA (the kind of RNA of which the Pfizer-BioNTech and Moderna vaccines are made), with a sequence of building blocks that corresponds to the DNA sequence from which it was made. That mRNA molecule is then transported outside of the nucleus, to the other main compartment of the cell known as the cytoplasm, where the mRNA sequence is read, or translated, by a structure called a ribosome to produce a protein.
Whereas the genes within the SARS-CoV2 virus consist of RNA, not DNA, the scientists of the AstraZeneca-Oxford team have written the spike protein recipe in DNA form and put that DNA into a type of virus called AAV. Unlike SARS-CoV2, AAV, of which there are numerous types, stores its instructions as DNA. In addition to inserting the engineered DNA for the spike protein into an AAV, the scientists also have removed the part of the AAV’s own DNA genome that allows it to be infectious. In this case, scientists have selected a particular AAV that normally infects chimpanzees to assure that the human immune system will not mount a response against the virus. After all, we don’t want the body to fight against the delivery vehicle for the vaccine; we want the body to fight the virus by recognizing the spike protein. Consequently, the AAV delivers the DNA recipe for the spoke protein into the cells of a person who receives the vaccine. The advantage of using an AAV, loaded with DNA payload, is that the vaccine is stable at refrigerator temperatures. It does not need to be stored at -20 degrees Celsius like the Moderna vaccine, or at -70 degrees Celsius like the Pfizer-BioNTech vaccine. This makes the AstraZeneca vaccine much more practical to deliver throughout the world, especially in regions lacking low temperature freezers on vehicles. Because of this, and because AstraZeneca agreed not to profit from the vaccine, the cost of the vaccine is also extremely low —$3 per dose— in contrast with the Modern and Pfizer-BioNTech vaccines running from $15-25 each.
There are some curious things that have happened in the research on the AstraZeneca vaccine that are worth noting. First, a few months ago, clinical trials had to pause because one volunteer receiving the vaccine developed a serious condition called transverse myelitis, which is inflammation of the spinal cord. Before the clinical research could continue, scientists had to prove that this serious condition was not the result of the vaccine, but a coincidence, which they did prove. Another thing is that the company probably will not be able to use chimpanzee AAVs as the viral carrier to immunize billions of people. More significantly in the sense that there is still more to be understood is a faux pas that led to a serendipitous discovery. Although AstraZeneca is British, the clinical trials have been conducted both in the UK and in Brazil. Scientists had worked out a particular dosage of the vaccine, given twice, the second dose about a month after the first, similar to the schedule of the Pfizer-BioNTech and Moderna vaccines. Whereas the volunteers in Brazil were given the vaccine according to protocol, which was shown to be 62 percent effective in stopping the virus from spreading and causing disease, in the UK the dosage of the first shot was accidentally cut in half and this turned out to be 90 percent effective! Now 62 percent effectiveness against spreading the virus to other people would already be a very good vaccine. But 90 percent —if this proves true when the data are published in peer reviewed studies— would be positively amazing. Now, since the vaccine does appear to be safe, including in the mistake protocol with the first dose cut in half, the mistake is not likely to slow the production and distribution of the vaccine. But it does leave scientists with a mystery —why does a smaller dose for the first of the two shots make it work better?— the study of which ultimately may lead to a new understanding of vaccine immunology, and ultimately still better vaccines for a range of illnesses.