Vanquishing the virus: the race to make vaccines for Covid-19
The extraordinarily rapid development of effective treatments against the coronavirus is a triumph of biotechnology, says Dr Mike Tubbs. He reviews the story and explains what it means for investors.
Many MoneyWeek readers will have had their first Covid-19 vaccine jab by now; a few will have had their second. The advent of the vaccines is a story of clever biotechnology deployed with lightning speed, illustrating the sector’s rapid development over the last two decades. The Covid-19 virus was only sequenced (genetically mapped) in mid-January 2020 and the first two vaccines approved in the UK were the Pfizer/BioNTec treatment in early December 2020 and the AstraZeneca/Oxford University one in late December – 11 and 12 months later respectively.
The International Federation of Pharmaceutical Manufacturers & Associations says that the normal timescale for vaccine development is between ten and 15 years. Prior to the Covid-19 vaccines, the record for vaccine development was four years for the mumps treatment, which emerged in 1967.
The Pfizer/BioNTec and Moderna vaccines use similar mRNA technology, whereas the AstraZeneca/Oxford one uses a viral-carrier approach. All three vaccines benefited from previous research on two other coronaviruses, Severe Acute Respiratory Syndrome (Sars), which emerged in China in 2003, and Middle East Respiratory Syndrome (Mers) which jumped from camels to humans in 2012. Covid, Sars and Mers are called coronaviruses because of the spikes on their surface that resemble a crown under the microscope.
The breakthrough in mRNA technology
The story of mRNA starts in 1990. Synthetic messenger RNA, or mRNA, is a clever variation on the natural RNA that directs protein production in the body’s cells. The promise of the technology has always been that a modified form of it could be injected into the body to transform body cells into drug factories producing the right antibodies (proteins developed by the body that defend the immune system).
This was the idea that Hungary’s Katalin Karikó had while she was at the University of Pennsylvania in 1990. Her grant applications to develop the technology were all rejected for the reason that synthetic RNA was known to be vulnerable to the body’s defences, so it could be destroyed before reaching its target cells and that could cause an immune response that might have serious consequences for some patients. But Karikó persisted and was even demoted by her university for not bringing in enough research grant money.
With a collaborator at her university, Drew Weissman, she solved the problem. Every strand of mRNA is made up of four parts called nucleosides, and one of these was triggering the immune response. Karikó’s solution was to replace the problem nucleoside with a slightly modified version to make an mRNA that could work its way into cells without triggering the problematic immune response. Karikó and Weissman described their discovery in several papers published in 2005 and later.
Surprisingly, it was only scientists at two small biotechs – the founders of Moderna and BioNTec – who realised the enormous potential of Karikó’s discovery and both set about exploiting it by developing the technology to make mRNA medicines. When Covid-19 came along they both realised that an mRNA vaccine could be effective against the new virus. The vaccine is just a piece of mRNA inside a coating. The mRNA contains the code for a protein of the spikes of the Covid-19 virus. So once the mRNA enters cells, the cells produce this virus protein and the immune system recognises it as a foreign molecule and the body produces antibodies to fight it.
The AstraZeneca/Oxford approach
The AstraZeneca/Oxford vaccine uses a different technology based on the use of a carrier virus, a virus used to insert a gene into cells. Genetic code of the Covid-19 spike-protein is added to the carrier virus so when the carrier virus enters body cells, the spike-protein’s genetic code makes the cells produce the surface spike protein of the coronavirus. This produces an immune response so the immune system can attack the Covid-19 virus should it later enter the body.
The AstraZeneca/Oxford vaccine uses a carrier virus that is a weakened form of the virus causing the common cold in chimpanzees. The carrier virus is in fact isolated from chimpanzee stools and has been genetically altered so it cannot multiply in humans. Oxford University had already used this carrier-virus technology to make candidate vaccines against flu and Mers. This enabled the team to make a flying start on developing their Covid-19 vaccine.
The Medicines and Healthcare products Regulatory Agency (MHRA) realised how important it was going to be to approve new vaccines as quickly as possible without prejudicing safety and therefore devised a new method of rolling approval. This involved the regulator examining clinical trial results as they came in rather than waiting until all results had been gathered before starting regulatory examination.
Covid-19 vaccines were also approved under emergency-use regulations requiring companies to conduct follow-up surveys to look for side-effects and monitor efficacy in the field. The MHRA approved the Pfizer jab on 2 December 2020 and the US Food and Drug Administration on 8 December. In terms of vaccine rollout in large countries the UK is leading with 18% of its population vaccinated by 9 February; the US follows with 9%. In the EU the figure is 2.4%-2.8%.
The problem with mRNA vaccines is that they must be stored and transported at very low temperatures. The Pfizer vaccine must be transported in dry ice (implying a temperature of -78 degrees centigrade) and stored between -80C and -60C. This compares with domestic freezer temperatures of -23C to -18C. Once the vaccine is removed from storage, it can be kept in a refrigerator (2C to 8C) only for up to 120 hours. These requirements make it difficult to use in less developed countries and in many doctors’ surgeries.
The Moderna vaccine, however, is less sensitive to heat and only requires storage at freezer temperatures (-25C to -15C). It can live in a fridge for up to 30 days. The AstraZeneca/Oxford vaccine, on the other hand, can be transported and stored at refrigerator temperature for at least six months. The AstraZeneca treatment costs £3 per jab in the UK. The Pfizer and Moderna jabs cost £15 and a reported £26 respectively. Clinical trials show that the Pfizer/BioNTec and Moderna mRNA vaccines are up to 95% effective from a week after the second dose. The AstraZeneca vaccine is up to 90% effective after two doses spaced well apart. Some of the clinical trial volunteers were given a half dose followed by a full dose and this was more effective than two full doses.
However, it transpired that the half-dose cohort were in fact given their second doses after a longer delay and it was probably the delay rather than the half-dose that increased effectiveness. This conveniently ties in with the UK government’s decision to delay second doses of all vaccines so they are given 12 weeks after the first. The AstraZeneca vaccine gives 76% effectiveness after the first jab.
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