The beginning of the end

d'Lëtzebuerger Land du 25.12.2020

The first outbreak of Covid-19 (coronavirus disease 2019), which is caused by SARS-Cov-2 (severe acute respiratory syndrome coronavirus 2), was reported in Wuhan, China, on December 31, 2019. We watched in horror as the subsequent Covid-19 pandemic rapidly affected both the health and the economy of the world. As of early December 2020, SARS-Cov-2 had infected more than 70 million people and caused the deaths of 1.6 million. Without safe and effective vaccines, the pandemic would continue to rage.

Fortunately, recent developments in the form of messenger RNA (mRNA) vaccines provide grounds for optimism. As one would expect, these developments are based on previous findings. On May 13, 1961, two papers in the journal Nature described the identification of mRNA, the intermediary between protein-encoding DNA in the cell nucleus and protein synthesis at ribosomes in the cytoplasm. Messenger RNA, which forms a cornerstone of the code of life, is short-lived. In 1990, the first successful use of in vitro transcribed mRNA was published, when reporter gene mRNAs were injected into mice and protein production was detected. A major problem with mRNA is that it triggers an inflammatory response. Then, in 2005, Katalin Karikó and Drew Weissman from the University of Pennsylvania showed that the incorporation of modified nucleosides can prevent this response. This finding, more than any other, paved the way for the production of mRNA-based vaccines. Messenger RNAs encoding a single protein provide a major advantage over live attenuated and killed viruses, in that there is no danger of infection. Moreover, they do not integrate into DNA, hence there is no risk of insertional mutagenesis.

So, if anything, RNA vaccines are safer than the vaccines we received as children. Of course, we all know that nothing in life is ever 100 per cent safe, but a cost/benefit analysis argues very strongly in favour of vaccination against SARS-Cov-2.

Never before has a vaccine been shown to be effective against infection with a coronavirus. The Sars epidemic, which was caused by Sars-Cov, ended on its own, before serious efforts at vaccine development were undertaken. The number of cases of Mers (Middle-East respiratory syndrome), which is caused by another coronavirus, did not justify large-scale efforts at vaccine production. Enter Sars-Cov-2 and BNT162b2 (a vaccine that was produced and tested thanks to a collaboration between the biotechnology company BioNTech and the pharmaceutical giant Pfizer). The vaccine is a lipid nanoparticle-formulated, nucleoside-modified mRNA encoding the full-length Sars-Cov-2 spike glycoprotein with two mutations that lock the protein in the prefusion conformation. The spike glycoprotein is essential for infection, because it binds to angiotensin-converting enzyme 2 on the cell surface, thereby mediating entry of the virus into target cells. A successful vaccine will prevent cellular entry of the virus.

Early clinical trials showed that BNT162b2 induces B cell and T cell immune responses. Unlike protein immunization, mRNA vaccines activate some T lymphocytes. We now know that BNT162b2 also protects against infection. In a multinational, placebo-controlled, observer-blinded efficacy trial, 21 720 persons 16 years or older received BNT162b2 and 21 728 a placebo. Both groups received two injections that were spaced 21 days apart. Eight cases of Covid-19 were observed in the vaccine group, as compared to 162 cases in the placebo group, resulting in an overall efficacy of 95 per cent. Thus, the immune response that we mount in response to injection of the mRNA encoding mutant spike glycoprotein prevents the entry of Sars-Cov2 into body cells with remarkable efficiency. Similar efficacies were present in low-risk and high-risk groups. Although this remains to be shown experimentally, it is likely that BNT162b2 will also be effective against current variants of SARS-Cov-2.

It is not yet known if those protected against infection through vaccination may still infect others. We do know, however, that around 60-70 per cent of a population need to be immune in order to render the spread of disease from person to person unlikely (herd immunity). Since this is bound to take a while, we will inevitably face major restrictions for the months to come.

Though most vaccines have taken decades to develop, BNT162b2 has moved from conception to large-scale implementation in less than a year. Its development began on January 10, when the genetic sequence of Sars-Cov-2 was released by the Chinese centre for disease control and prevention; BNT162b2 was approved for widespread use by the UK MHRA (Medicines and healthcare products regulatory agency) on December 2 and received Emergency Use Authorization by the US FDA (Food and drug administration) on December 11. Approval by the EMA (European medicines agency) was granted on December 21.

A second mRNA vaccine, produced and tested by the biotechnology company Moderna, received Emergency Use Authorization by the FDA on December 18. Approval by the MHRA of a third vaccine, produced and tested in a collaboration between the Jenner Institute at Oxford University and the pharmaceutical giant AstraZeneca, is imminent. That several safe and effective vaccines, which protect from COVID-19, were produced in less than a year is a triumph of biomedicine. The journal Science has chosen these “Shots of Hope” as the “Breakthrough of 2020”. It has been stunning to see that the work of ten years was done in under eleven months.

Messenger RNA-based vaccines are now major tools to combat COVID-19 and similar diseases. We must not forget that there have been two coronavirus epidemics and one pandemic in the past 20 years. It would, no doubt, be foolish to believe that there will be no others.

Michel Goedert is member of the Conseil de gouvernance of the He is a programme leader at the Medical Research Council Laboratory of Molecular Biology and an Honorary Professor of Experimental Molecular Neurology at the University
of Cambridge, UK

Michel Goedert
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