Weighing in on the saga of a vaccine

The AstraZeneca story shows that in research and development, logistics, transparency and communication also count

Updated - March 29, 2021 12:56 am IST

Published - March 29, 2021 12:02 am IST

The AstraZeneca SARS-CoV2 AZD1222 vaccine, which was developed at the University of Oxford, is a chimpanzee adenovirus strain which was engineered so that it could not replicate any more in humans. The team at Oxford had already begun to use this chimpanzee adenovirus vaccine technology to produce candidate vaccines against many pathogens including influenza, Zika and the Middle East Respiratory Syndrome coronavirus.

When work began

They had also begun, with the Coalition for Epidemic Preparedness Innovations (CEPI), to use this technology in preparation for ‘Disease X’. When the sequence of SARS-CoV2 was released in January 2020, they moved very quickly to engineer a new candidate vaccine and begin work on a trial. Sarah Gilbert who led the team with others at the University of Oxford and the Jenner Institute announced very early on that she thought that we would have a vaccine available by October. This was really quite remarkable given that everyone else was predicting that we would not have vaccines available for at least 12 to 15 months.

The team at Oxford and the Jenner had been working for a long time on candidate vaccines, and had the capacity to make pilot lots for clinical trials, but they did not have the capacity to make vaccines at scale, particularly those that would require millions or billions of doses. So, working with CEPI and the Bill and Melinda Gates Foundation, the Oxford team began discussions with multiple companies in order to figure out who could be a manufacturing and development partner for the vaccine. Initially, it was thought that it might be possible to engage with Merck, an American leader producing vast amounts of vaccines, but ultimately it was decided to go with AstraZeneca, a company that had no experience of vaccines other than a nasal flu spray, but was a British-Swedish pharma conglomerate.

The vaccine began to be tested in humans in April 2020 and technology transfer agreements were agreed with SKBio in South Korea and the Serum Institute of India, and others; the goal was to make a vaccine that was suitable for use in immunisation programmes around the world and could be made at very large volumes. By December we had results that indicated the vaccine worked.

Interpreting the vaccine data

But before and after December, it has been an incredibly bumpy road for AstraZeneca. Before the trial results became available, the trial was stopped for a while to investigate a case of transverse myelitis in the United Kingdom. In India, a case of neurolupus led to questions about the responsibilities of investigators, sponsors and regulators. When the results were announced in December, the first report was by press release and indicated an efficacy of 70%, with some peculiar results showing that in some groups, efficacy could be as high as 90%. It first turned out there were several issues. The vaccine trials compared a single dose and two doses, and decided to go with two doses, but with supply issues, wound up with some people with a single dose and others with two doses, but with varying intervals because there were long gaps while waiting for supply initially, and then closer to the originally proposed four week interval as enough vaccine became available.

To complicate matters further, there was an error in calculating doses, and some individuals had received vaccine doses that had less of the viral vector. Initially, it was reported that highest efficacy was seen with a lower first dose, and scientists scrambled to try and find an explanation. It was hypothesised that it might be because antibodies made in response to the first dose inhibited response to the second dose, but given that the difference was one of 25 billion and 50 billion viral particles, it seemed a bit unlikely.

Later, as more data became available, it was clear that the longer time there was between doses, the immune response and efficacy were better. But considerable damage had already been done because of the messy sequential communications, even though results from multiple analyses were being rapidly published by the Oxford team.

The vaccine data were reviewed by the regulator in the United Kingdom, the Medicines and Healthcare Products Regulatory Agency, which gave emergency use authorisation, and the Joint Committee on Vaccination and Immunisation recommended initiation of vaccination in the U.K. with a 12 week gap. The data were reviewed by the World Health Organization (WHO) and the European Medicines Agency (EMA) which also approved the vaccine and recommended its use. Since this vaccine was suitable for use within routine immunisation programmes, this was a reason to celebrate, because Serum, SKBio and AstraZeneca had all committed to making the vaccine available to the COVAX facility which is committed to providing vaccines to at least 20% of the world’s population, irrespective of the ability to pay.

The case in Europe

Unfortunately, the controversies continued. A few European countries refused to use the vaccine in older individuals, citing the lack of data from this subset in clinical trials. And then, cases of haematological side-effects which combined blood clots and low platelets began to be reported. So far, the data do not indicate a signal of side-effects that are above the baseline of thromboembolic events, but in a limited number of cases, the clinical picture is unusual and has been labelled vaccine-induced prothrombotic immune thrombocytopenia by researchers in Norway and Germany. This will continue to be investigated until we understand the association and the level of risk, but it is clear, and stated by the EMA and WHO, that the benefit far outweighs any rare risk.

Even as the vaccine began to be widely used, the global community awaited trials of the vaccine in the U.S. and South America under Operation Warp Speed, and when a press release in March stated 79% efficacy, there was a sense of relief that, finally, clean and clear data from a study that included 32,000 people were available.

This was followed swiftly by an unusual announcement by the U.S. government’s National Institutes of Health to say that the Data and Safety Monitoring Board (DSMB) felt it essential to report that the data were outdated. The company said that they were reporting data until February 17 based on 141 cases and scrambled to get a fuller analysis of 190 cases showing an efficacy of 74% which was released last week. This throws up a lot of questions about why the DSMB felt it essential to bring this up, when other companies like Moderna and Pfizer had also reported first interim and then final results. In any case, the data will be independently reviewed by the Food and Drug Administration, the U.S. regulator, and then perhaps all the controversies can finally be put to rest.

This vaccine has potential, but if this saga highlights anything, it is that in clinical research and development, logistics, transparency and communication matter as much as the science.

Gagandeep Kang is Professor,Christian Medical College, Vellore

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