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The story behind COVID-19 vaccines

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Amidst the staggering amount of suffering and death during this historic pandemic of COVID-19, a remarkable success story stands out. The development of several highly effective vaccines against a previously unknown viral pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in less than 1

year from the identification of the virus is unprecedented in the history of vaccinology. A frequently asked question is how such an extraordinary achievement could have been realized in such a short time frame when timelines for other vaccines are measured this year, if not decades. In fact, concern over this shortened timeline has in part contributed to the reluctance to accept these vaccines. What is not fully appreciated is that the starting point for the timeline of SARS-CoV-2 vaccines was not January 10, 2020, when the Chinese published the genetic sequence of the virus. Rather, it began decades outside the limelight.

Two activities prior to the successful COVID-19 vaccines: the use of highly adaptable vaccine platforms such as RNA (among others) and the adaptation of structural biological tools to design agents (immunogens) that strongly stimulate the immune system. The RNA approach evolved over several years due to the ingenuity of individual researchers, including Drew Weissman and Katalin Karikó, and the concentrated efforts of several biotechnology and pharmaceutical companies.

The discovery of a multi-platform immunogen (messenger RNA and others) used for COVID-19 vaccines was the result of collaboration across different scientific subspecialties. At the Vaccine Research Center (VRC) of the US National Institute of Allergy and Infectious Diseases, a group led by Peter Kwong had for several years used tools with structure-based vaccine design to determine the optimal structural conformation of a trimer protein on the surface of the virus (coat protein). enables HIV to bind to cells and ultimately trigger the production of antibodies that neutralize many HIV virus strains. Although this sophisticated approach has not yet led to a successful HIV vaccine, it caught the attention of another VRC investigator, Barney Graham, who was interested in generating a vaccine against respiratory syncytial virus (RSV). Graham joined Jason McLellan (from Kwong’s team) to adapt a structured approach to an RSV vaccine. They identified the prefusion conformation of the viral spike protein as highly immunogenic and created mutations to stabilize this conformation for successful use as an immunogen. This was a major step towards the creation of a successful RSV vaccine.

VRC researchers and colleagues then built on RSV progress. Graham’s team, including Kizzmekia Corbett, and collaborators in the laboratories of McLellan and Andrew Ward adopted this approach to mutational stabilization of prefusion proteins in their work with the spike protein in coronavirus, which causes Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). So when the genetic sequence of SARS-CoV-2 became available, Graham’s team lost no time in joining their long-standing collaborators in Moderna to develop an RNA vaccine using a stabilized, prepositional tip protein as an immunogen. Pfizer and BioNTech, where Karikó worked, also used the RNA platform she and Weissman had perfected, and the immunogen designed by Graham to develop an RNA vaccine. Additional companies also used Graham’s immunogen in other vaccine platforms that had evolved over the years to manufacture SARS-CoV-2 vaccines.

SARS-CoV-2 vaccines based on the new immunogen moved rapidly to clinical trials. Several of these vaccines were tested in Phase 3 efficacy trials at a time when the level of societal spread of SARS-CoV-2 was extremely high, allowing vaccine efficacy endpoints to reach more than 90% in a timely manner. The speed and effectiveness with which these highly effective vaccines were developed and their potential to save millions of lives are due to an extraordinary interdisciplinary effort involving basic, preclinical and clinical science that had been going on – out of the limelight – for decades before unfolding. of the COVID-19 pandemic. Once the stories and narratives of this pandemic are written, it is important that this story is not forgotten, as we are once again reminded of the societal value of sustained and robust support for our scientific enterprise.

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