Serendipity Led to Oxford/AstraZeneca Vaccine’s 90% Efficacy Rate

The half-dose/full dose puzzle in the results is explained.

7 min readNov 29, 2020

Image: COVID-19 Vaccine Photo by Daniel Schludi via Unsplash

The researchers at AstraZeneca and Oxford University reported on Monday, November 23, 2020, that their COVID-19 vaccine is 70% effective. This announcement, coming on the heels of promising news from Pfizer/BioNTech and Moderna about their vaccines, raises hope that a new vaccine to fight the COVID-19 pandemic may soon become available. Links to two prior stories on Medium can be found at the bottom.

According to AstraZeneca’s press release, the results from the interim analysis of clinical trials of the vaccine AZD1222 in the UK and Brazil showed it was highly effective in preventing COVID-19. Among the participants who received the vaccine, none required hospitalization or suffered a severe case of COVID-19. The researchers also say that their vaccine may reduce the virus’s transmission. The other two vaccines did not report such an outcome.

Two dosing regimens were used in the clinical trials. The 2,741 participants in one of the regimens received a half dose of the vaccine initially, followed by a full dose at least one month apart. The results showed a 90% efficacy. The second dosing regimen with 8,895 participants showed 62% efficacy when given two full doses at least one month apart. The combined analysis from both dosing regimens (11,636 participants) resulted in an average efficacy of 70%. Only 131 participants came down with COVID-19, according to the interim analysis.

The Economist reports that the Oxford/AstraZeneca vaccine would be cheaper to produce and more convenient to distribute to developing countries in Asia and Africa. The reason being it can be stored and transported at average refrigerated temperatures of 2 degrees to 8 degrees Celsius (36 degrees to 46 degrees Fahrenheit).

AstraZeneca has partnerships to produce the vaccines globally, including India, Latin America, Russia, and Thailand. The Serum Institute, an Indian maker of drugs and vaccines, is committed to mass-manufacturing the AstraZeneca vaccine through a partnership with the Bill & Melinda Gates Foundation and Gavi, the international alliance to provide vaccines in developing countries. It would be sold at $3 (Indian Rupees 250) per dose, as reported by the Hindustan Times. In comparison, in the USA, the Pfizer vaccine’s initial doses would cost $19.95 and the Moderna vaccine between $25-$37 (Indian Rupees from 1,500 to 2,750). Since the US government has made arrangements to buy the vaccines or subsidized their development, the US taxpayers would initially receive them free. If approved, AstraZeneca expects to produce three billion doses in 2021 at different sites around the world.

According to the interim report, the Oxford/AstraZeneca vaccine was well tolerated by those who received it. An adverse event temporarily halted the clinical trials in the U.K. earlier this year. Regulatory agencies will consider this and other questions when they assess applications for emergency authorization. AstraZeneca says it will also seek an emergency listing from the World Health Organisation. That will allow them to use its jabs in countries without regulatory authorities capable of assessing vaccines.

AstraZeneca vaccine reported being safe and effective for older adults.

The British medical journal, Lancet, on November 18, 2020, published a peer-reviewed article that analyzed data from the Phase 2/3 trials of the Oxford/AstraZeneca vaccine administered to 560 healthy adults that included 160 participants aged 56–69 years and 240 over the age of 70-years. This study was conducted between May 30 and August 8, 2020, and found the vaccine safe and produced a similar immune response among people aged 56–69 and those in the 18 to 55 age group. Dr. Maheshi Ramasamy, the lead author of the study, said the antibody and T-cell responses among older adults were “robust” and “encouraging.”

CNN Video via YouTube

CNN’s Becky Anderson speaks with Professor Adrian Hill, director of Oxford University’s Jenner Institute, about the clinical trials for AstraZeneca’s vaccine and the results. Prof. Hill says that the vaccine prevented asymptomatic carriers from spreading the virus. We have to wait for more detailed data to ascertain the claim. The adenovirus vector platform technology has been in use since the 1990s and has been deemed safe in other vaccines.

The half-dose full dose puzzle

The participants who received two full doses of the vaccine showed an efficacy rate of 62.4%, while those who received the half-dose followed by full dose showed a 90% rate. This anomaly in the results perplexed virologists. The British tabloid, Mirror reported on June 15, 2020, that the Oxford scientists accidentally gave clinical trial participants the wrong dose. The university checked with the Medicines and Healthcare products Regulatory Agency (MHRA) who allowed them to continue with the changed dose.

Viral vector

Image Courtesy: Oxford University

The Oxford–AstraZeneca vaccine is made from ‘adenovirus’ isolated from the stool of chimpanzees and then modified so that it will not replicate in cells. When injected, the vaccine instructs human cells to produce the SARS-CoV-2 spike protein — the immune system’s main target against coronaviruses.

Ewen Callaway has an excellent write up in the magazine Nature, published on November 23, 2020. He discusses at length the current theories about the half-dose/full dose puzzle.

Dosing theories

The differences in efficacies between the two immunization regimens appear to be statistically significant. Katie Ewer, an immunologist at Oxford’s Jenner Institute, does not think it is an anomaly. She has two theories for why a lower first dose might have led to better protection against COVID-19.

Lower doses of the vaccine may do a better job at stimulating the subset of immune cells called T cells that support the production of antibodies.
The second theory is the immune system’s response against the chimpanzee virus. The vaccine triggers an immune response to the SARS-CoV-2 spike protein and the viral vector components. The full first dose created a more robust immune response to the adenovirus vector. When the participant receives the second dose of the vaccine, the immune system could have jumped into action and eradicated the adenovirus before it had a chance to express the SARS-CoV-2 spike protein. Dr. Anthony Fauci of NIH agrees with this hypothesis. He is quoted as saying, the smaller initial dose may “tickle” the immune system enough to generate T cells, but not trigger the development of antibodies that might work to suppress the response to the booster shot.

As reported in the magazine Science on November 25, 2020, there is some evidence to suggest slowly increasing the dose of a vaccine closely mimics a natural viral infection, leading to a more robust immune response. Prof. Adrian Hill of Oxford University is quoted as saying, “It’s not really mechanistically pinned down exactly how it works.”

Hildegund Ertl, a viral immunologist at the Wistar Institute in Philadelphia, thinks that a lower first dose leads more quickly to establishing ‘memory’ immune cells. A second-dose boost then triggers these memory immune cells.

The Oxford researchers’ wrong dose accident might have led to higher efficacy of the vaccine. The reduction of two full doses to one and a half doses will make it possible to vaccinate a third (33%) more people. It will be welcome news for the millions of people worldwide waiting for a cheap and effective vaccine to combat the pandemic.

Serendipity has played a role in medical innovations. The discovery of penicillin is the best-known example. In 1928 Sir Alexander Fleming, a professor of bacteriology, noticed mold had started to grow on the petri dishes of Staphylococcus bacteria colonies. While trying to salvage the bacteria from those infected with the mold, he saw something intriguing. The mold turned out to be a rare strain of Penicillium notatum, which secreted a substance that inhibited bacterial growth. It was from this mold, Dr. Fleming prepared the antibiotic penicillin.

As a scientist, my dream is for more such accidents to occur, leading to more serendipitous discoveries.