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Covid19 Vaccine oxfordAZ

 

Soon after University of Oxford and AstraZeneca PLC’s announcement that their COVID-19 vaccine AZD1222 showed 70% efficacy in interim results from Phase III trials, their Indian partner, Serum Institute of India Pvt. Ltd., revealed that it also cut virus spread by 60%.

In the global study conducted by the UK partners, “There were zero hospitalizations in the vaccinated group and the vaccine also brought down by 60% spreading of the virus. So, it grants sterilizing immunity as well and the vaccinated group does not infect others. We don’t know this number for the other [competitor] vaccines,” said Adar Poonawalla, the CEO of Serum Institute.

Epidemiologist and molecular biologist Dr Hemanth Kumar Manikyam points out that prevention of transmission is an important criterion and data on this parameter should also be considered while evaluating a vaccine.

How Infectious Is COVID-19?

A “personal view” published in the The Lancet on 3 July 2020 by authors from the European Society for Clinical Microbiology and Infectious Diseases in Basel, among others, gave these data on SARS-CoV-2’s transmissibility: 

The basic reproductive rate (R0) for SARS-CoV-2 is estimated to be 2·5 (range 1·8–3·6) compared with 2·0–3·0 for SARS-CoV and the 1918 influenza pandemic, 0·9 for MERS-CoV, and 1·5 for the 2009 influenza pandemic.

“How good a vaccine is can be nebulous. Efficacy refers to how good a vaccine is under optimal conditions of trial design, or inclusion/exclusion criteria and effectiveness refers to the real-world experience.

"It’s important to understand that a vaccine can do one or both of preventing transmission altogether and reducing or preventing symptoms but not preventing transmission,” he told Scrip.

This data is usually a secondary endpoint in vaccine trials and until such time that companies publish detailed trial data, it will not be publicly available.

Pfizer Inc./BioNTech SE and Moderna, Inc. have claimed over 90% efficacy for their respective COVID-19 vaccines, but external experts are unlikely to comment on these figures until the full dataset is delivered to regulators and published in a peer reviewed journal.

The ability of a vaccine to prevent the spread of SARS-CoV-2, the virus causing COVID-19, also gains significance against the backdrop of a comment by Tedros Adhanom Ghebreyesus, director-general of the World Health Organization (WHO) that a vaccine would not by itself stop the coronavirus pandemic.

"A vaccine will complement the other tools we have, not replace them. It will still leave the virus with a lot of room to move. Surveillance will need to continue, people will still need to be tested, isolated and cared for, contacts will still need to be traced," he said. 

Dosing Results Explained

Meanwhile, Oxford/AZ’s results of the lesser dose of its vaccine being more effective left the common observer a little puzzled. (Also see "Oxford/AZ Vaccine Hits 70% Efficacy In Phase III Trials" - Scrip, 23 Nov, 2020.)

The UK-based CV002 study on 2,741 participants produced a 90% effective result in a group of patients receiving a half-dose prime injection followed by a full boost dose at least a month apart. In contrast, 8,895 participants given two full doses at least a month apart across both UK and Brazil trials produced 62% efficacy.

Well-known virologist and clinician-scientist Dr Gagandeep Kang explained the results in a twitter thread, saying a complicated prime-boost could have led to the lesser dose being more effective.

“Prime-boost vaccine strategies try to enhance cellular and antibody immunity for longer and stronger protection. Prime-boost is complicated - selection of antigen, type of vector, delivery route, dose, adjuvant, boosting regimen, the order of vector injection, and the intervals between different vaccinations influence outcome,” she cautioned.

More data are needed to understand whether this is just a UK/Brazil difference she said, adding there is a lot still not understood about human immunology, and the pandemic is “making us learn and fast.”

Dilemma For Serum

Whatever the reason, the different set of results has placed India's Serum Institute in a conundrum. The company is nearing completion of dosing for the vaccine, named Covishield and based on technology transfer from Oxford/AstraZeneca, in Phase II/III clinical trial participants in India.

However, the protocol for the trial in 1,600 participants is a two-dose schedule given on day 1 and 29 as a 0.5ml dose. One comparator arm is the Oxford/AZ vaccine while the other is a placebo, both administered as two doses with the same frequency and dosage as Covishield.

Given that the half-dose prime injection followed by a full boost dose has yielded better efficacy than this regimen, Serum now faces a dilemma when it applies for marketing approval should results from the Phase II/III study in India be positive.

Indian guidelines on COVID-19 vaccines specify a minimum 50% efficacy for SARS-CoV-2 vaccines as the primary endpoint, so both dosing regimens meet the minimum requirement. (Also see "India’s Draft Guidelines For COVID-19 Vaccines Follow WHO, US Lead" - Pink Sheet, 24 Sep, 2020.)

While approval for the two-dose regimen will be easier as this is the one studied among Indian subjects, it could be less acceptable on account of lower efficacy. If the application is for the one-and-a-half dose regimen, the Drugs Controller General of India (DCGI) might be more reluctant to grant approval as this was not part of the local trial protocol. Poonawalla said a dosage regimen will be finalized after the Indian trial is complete.

“Once the regulatory bodies in India and around the world are confident of the vaccine's safety and efficacy, only then can we look towards emergency authorization,” he told Scrip in response to a question on whether and when a restricted use authorization will be sought.

Serum will complete dosing of all participants by mid-December and expects to submit data from this trial, as well as from the Oxford/AZ trials, by end-December. It hopes to begin supplying the vaccine to the Indian government for immunizing healthcare workers and at-risk population subsets by January or February and a full approval for the general populace should follow thereafter.

Manufacturing, Supply, Pricing

Meanwhile, Serum has already manufactured 40 million doses of Covishield at-risk under an agreement with Oxford/AZ even before approval has been obtained. 100 million doses are to be ready by January and the intention is to manufacture 60-70 million doses, stretching up to 100 million doses by February 2021.

“Whatever quantity we manufacture, half of it will be reserved for India and the remaining will go to low- and middle-income countries,” Poonawalla told Scrip. The supply to low- and middle-income countries will be under an agreement with the Bill & Melinda Gates Foundation and the Covax facility.

While a draft purchase agreement with the Indian government is yet to be signed, Serum Institute has the right to supply the Oxford/AZ vaccine to 68 countries. In a tweet on 23 November, the University of Oxford said it hopes to supply three billion doses of the vaccine globally by the end of next year.

“We have stayed away from bilateral agreements with other countries so far because we need to take care of India and Covax requirements first. An agreement with Bangladesh, if signed, will require us to supply 30 million doses. Bilateral discussions on vaccine diplomacy will be held through the Indian government,” he explained. 

Top diplomats from over 20 countries are to visit the manufacturing facilities of Serum Institute and Gennova Biopharmaceuticals in Pune, India this week as the country launches an international vaccine diplomacy initiative, a local media report indicated.

Unlike the optimal storage temperature of -60 to -90 degrees Celsius needed for the Pfizer/BioNTech mRNA vaccine, -20 degrees for the Moderna vaccine and -18 degrees for the standard Sputnik V vaccine, the Oxford/AZ vaccine can be stored, transported and handled at 2-8 degrees Celsius (the same range as the lyophilized version of the Russian vaccine). This makes it more suitable for developing countries as it can be stored in normal refrigerators.

Besides, it will be available at a lower cost than Pfizer, Moderna or Gamaleya Research Institute’s vaccine. Serum Institute has committed to supplying the vaccine to Gavi, the vaccines alliance, at a maximum of $3 a dose for immunization programs across developing countries, which is also the price at which it is expected to supply to the Indian government. (Also see "Russia Prepares $10 COVID-19 Vaccine For International Launch" - Scrip, 24 Nov, 2020.) 

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