Thread by @AlbertoEspay

The success of #COVID19 vaccines required heavy investments into #HIV research and the resourcefulness and creativity of many. The 60-year history summarized by @nytimes highlights important lessons. (1/12)

nytimes.com/2022/01/15/hea…

(2/12) 1st milestone: 1960 – “Molecule X” carried copies of DNA segments to ribosomes to make proteins. It is posited to be the "messenger" RNA, or mRNA. Could this molecule be instructed to make tiny pieces of viruses to strengthen the immune system?

(3/12) 2nd milestone: 1960-2005 – Exogenous mRNA was easily degraded by the immune system, treated as an invading pathogen. Native mRNA, it was discovered, is protected with a specific modification. Doing that allowed mRNA delivery without provoking an immune response.

(4/12) Katalin Karikó, a Hungarian immigrant who had devoted her life to mRNA, knew it could be protected from degradation. Her labor of love, under the supervision of Drew Weismann, was rejected by Nature and Science –but has been cited 1330 times.
tinyurl.com/29sd3j58

(5/12) 3rd milestone: 1981-2017: Dr. Fauci’s leadership on HIV research convinced President Bill Clinton to launch the NIH Vaccine Research Center to create a vaccine targeting HIV spikes. Eighty-five trials later, there was no HIV vaccine but much knowledge on mapping spikes.

(6/12) In 2008, 27-year-old Jason McLellan, who studied X-ray crystallography, joined the HIV laboratory of structural biologist Peter Kwong. Soon after, he asked to work on “a more manageable virus”. Virologist Barney Graham, also at the NIH, was working on RSV.

(7/12) The cold-causing respiratory syncytial virus and the SARS-CoV-2 coronavirus feature RNA genomes. McLellan and Graham’s knowledge of the structure of the protein that RSV uses to fuse with cells proved critical for understanding a future SARS-CoV-2 fusion.

(8/12) The MERS-CoV and SARS-CoV-1 epidemics made visualizing the “wobbly” spikes of coronavirus an urgent gap to bridge. Structural biologist Andrew Ward led the work to capture the structure of HKU1 spike, a mild coronavirus, for the first time.
nature.com/articles/natur…

(9/12) Nianshuang Wang, a postdoc from China, came to work with McLellan to help figure out how to stabilize MERS-CoV spike proteins. Guided by the HKU1 map, the addition of two prolines (“2P mutation”) solved the problem.
doi.org/10.1016/j.celr…

(10/12) After Chinese researchers posted the virus’s genetic sequence online in January 2020, McLellan and Wang applied the 2P mutation on the SARS-CoV-2 spike, releasing the data online. Pfizer and BioNTech began using that 2P mutation in their vaccines.
science.org/doi/10.1126/sc…

(11/12) By early 2020, the spike of SARS-CoV-2 was encoded in mRNA molecules, wrapped in a protective layer of fat, and poured into small glass vials. They were shot into arms less than a year later.

(12/12) In sum, the success of the COVID-19 vaccines relied on: (1) discovering and understanding mRNA, (2) knowing how to prevent its degradation, (3) many HIV vaccines "failures," (4) talented young scientists from Hungary and China, and (5) a deep international collaboration.