Week's news analysis

Where are the European-manufactured
vaccine doses going?

by the editor - 23 March 2021


Last year, much of Europe's leaders watched with dismay as the UK and US governments struggled to deal with the pandemic. The roles quickly changed, with the UK now administering over 40 doses of vaccine per 100 people and the US over 34 doses per 100 people. Within two days, last week, the United States succeeded in vaccinating 6 million people! The European Union administered a first dose to 10.4% of the population only on March 19, 2021 and 4.5% of the population received two doses of the vaccine. The European Union is unlikely to catch up with the United States or the United Kingdom in the short term.

The European Commission has announced a global order quantity of 1,860 million doses for the first four vaccines on the European market: 600 million doses for Pfizer / BioNTech, 460 million doses for Moderna's vaccine, 400 million doses for the vaccine Astra Zeneca and 400 million doses for Janssen's vaccine (just one dose administered)... enough to vaccinate the 340 million people over 18 years out of the 448 million people in Europe several times. However, to understand the existing situation it is necessary to go back in detail to the history of the planning of these orders, the implementation of mass production of vaccines and the associated logistics.

Many government administrations in the 27 countries have found bitterly that the EU's vaccination campaign is lagging behind that of the US and UK, in part due to massive shortages of deliveries from European locations from Astra Zeneca and UK. The Anglo-Swedish company caused the furor, revealing to the commission and member states of Europe on January 22 that it would deliver less than a third of the 100 million doses expected by the European Union at the end of March. Many difficulties can arise when starting the production of a vaccine. Especially since the new technology used for AstraZeneca's vaccine is innovative. And it is necessary to remove many obstacles before ensuring productions with a stable process.

However, the quantities ordered from AstraZeneca by the EU represent only 400 million doses out of the 1,850 million doses totaled by orders placed with Pfizer / BioNtech, Moderna and AstraZeneca. How can we explain, then, that orders for 1060 million remaining doses between Pfizer / BioNtech and Moderna are reaching us in such small quantities and with delay in the first quarter of 2021?

In the second quarter the European Commission expects the delivery of 35 million doses to Europe. However, the industrial capacities of Fill and Finish for the second quarter of the CDMOs: Rovi (based in Spain in Madrid) and Recipharm (site based in France in Monts) which condition the Moderna product total more than 140 million doses. How to explain such a gap? What are the destinations of more than 100 million doses of Moderna's vaccine for the second quarter of 2021?

In order to find an explanation, it seemed interesting to us to compare on the one hand the history of the orders placed by the European Commission, the deliveries made by the laboratories in the first quarter, the delivery forecasts in the second quarter and on the other hand the quantities produced by pharmaceutical laboratories.

Order history by the European Commission

The first contract signed by the European Commission on August 27, 2020 was for the purchase agreement for 300 million doses of the AstraZeneca vaccine, with an option for 100 million additional doses, to be distributed on a pro-rata basis. Discussions between Moderna and the European Commission began in August 2020 for the supply of 80 million doses. On November 25, after 4 long months of discussion, the committee finally decided on an agreement with Moderna to secure the supply of 80 million doses and a second reservation for 80 million optional doses. In the month of November, prior to the agreement with the European Commission, Moderna signed an agreement with the UK for a supply of 5 million doses. On November 29, the UK secured an additional 2 million doses. As of February 25, 2021, the UK had secured 17 million doses.

A contract was signed on October 7, 2020 with Janssen for the delivery of 200 million doses of its single-dose COVID-19 vaccine to the EU from the second quarter of 2021.

On 11 November 2020, the European Commission approved the contract with Pfizer / BioNTech, which provided for the initial purchase of 200 million doses on behalf of all EU Member States, plus an option to purchase up to a further 100 million doses, to be supplied once a vaccine has proven to be safe and effective against COVID-19.

On November 16, Moderna announced that its COVID-19 vaccine candidate remained stable between 2 ° and 8 ° C (36 ° and 46 ° F), the temperature of a standard household or medical refrigerator, for 30 days and at room temperature up to 12 hours. MRNA-1273 remained stable at -20 ° C (-4 ° F) for up to six months, which was not the case with the Pfizer / BioNTech vaccine which required very low temperatures (-80 ° C) ... ... This Moderna announcement was important because it greatly simplified the organization of logistics for the deployment of the vaccine to the medical profession and pharmaceutical networks. However, this vaccine has not been selected by many countries including France for vaccination through pharmacy networks.

On December 4, Israel ordered 4 million additional doses from Moderna and therefore secured 6 million doses. On December 8, it completed its order of two million doses for a total quantity of 7.5 million doses.

On December 15, 2020, the Commission decided to purchase these additional 100 million doses from Pfizer.

On December 17, Moderna received an FDA grant of an Emergency Use Authorization (EUA) for its COVID-19 vaccine candidate, mRNA-1273.

On December 18, the European Commission has exercised its option to purchase an additional 80 million doses of mRNA-1273, Moderna's COVID-19 vaccine candidate, bringing its confirmed order commitment to 160 million doses.

On 21 December 2020, the European Commission granted a conditional marketing authorization for the COVID ? 19 vaccine developed by BioNTech and Pfizer, making it the first COVID-19 vaccine authorized in the EU.

On December 31, Moderna finalized the agreement with South Korea for the supply of 40 million doses. According to this agreement, the delivery of the doses will start in May 2021.

On January 4, 2021, Moderna, Inc. announced that the Israeli Ministry of Health (MOH) has given permission to import the COVID-19 Moderna vaccine into Israel.

On January 6, 2021, Moderna, Inc. announced that the European Commission had granted a Conditional Marketing Authorization (CMA) for the COVID-19 vaccine Moderna, allowing the deployment of vaccination programs using the Moderna vaccine across the European Union. The authorization was based on the recommendation of the European Medicines Agency (EMA) for the use of the COVID-19 Moderna vaccine for active immunization to prevent COVID-19 caused by the SARS-CoV-2 virus in people aged 18 and over.

On January 13, the EU's main vaccine contract negotiator, Sandra Gallina, defended the EU's collective approach to vaccines, arguing that doses purchased collectively "will come first", before those guaranteed in the framework of bilateral agreements. The EU prohibiting member states from negotiating individually.

The week before, Germany said it had secured an additional 30 million doses of the vaccine for its own citizens under a separate deal with BioNTech. The controversy swelled in some member states arguing that EU supplies were "not sufficient for rapid and massive vaccinations". The EU's main negotiator on vaccine contracts, Sandra Gallina said at the time that Brussels was buying "as much as it was offered", given prices and delivery times. Members of the European Union expressed their concerns to the head of the Commission about the lack of transparency regarding vaccine contracts. The announcement of these contracts had raised both high expectations and uncertainties regarding the delivery schedules negotiated by the commission.

As of January 13, BioNTech-Pfizer and Moderna vaccines were the only vaccines authorized in the EU. Vaccines delivered from January are distributed to EU countries in proportion to the population. However, several countries are expressing their preferences for the AstraZeneca vaccine as soon as it becomes available. This will call into question the balance of the proportions of vaccines distributed between the different countries of the European community.

On 29 January 2021, the European Commission granted a conditional marketing authorization for the vaccine against COVID-19 developed by AstraZeneca, making it the third vaccine authorized for use in the EU.

On February 3, Moderna, Inc. announced that the Swiss federal government had increased its confirmed order commitment from 7.5 million to 13.5 million doses of the COVID-19 Moderna vaccine in Switzerland. On February 9, 2021, Moderna, Inc. entered into an agreement one with the Taiwan government for 5 million doses and another with the Colombian government for 10 million doses. Under the terms of the agreements, deliveries would begin in mid-2021.

February 17, the European Commission finally announced the purchase of 150 million additional doses of the COVID-19 Moderna vaccine, the delivery of which is scheduled for the third and fourth quarters of 2021. This brings its confirmed order commitment to 310 million doses for delivery in 2021. Under the agreement, the European Commission has the option to purchase 150 million additional doses to be delivered in 2022.

From the point of view of the European Commission, this approach can, in theory, guarantee the lowest prices for the 27 member states. In order to guarantee the lowest prices, the negotiations were tedious and longer than expected. During these negotiations, the European Community dedicated an envelope of 2 billion 900 million aid to the laboratory to increase as quickly as possible the production capacities of vaccines in Europe. Negotiations delays contributed to delaying orders and therefore delivery priorities compared to states outside the European Union, which did not hesitate to pay a high price. These states have arranged deliveries of vaccines more quickly, especially UK and Israel.

The UK was the first country outside of the US to approve the Pfizer-BioNTech COVID-19 vaccine on December 2, 2020, and subsequently rolled out the AstraZeneca-Oxford and Moderna vaccines. The EU, however, did not approve the Pfizer-BioNTech vaccine until December 20. As of February 15, more than 15 million people in the UK have received at least one dose of the vaccine; around 23% of UK citizens compared to 10% on average for EU countries on March 19.

As for allegations that the EU has been too slow to sign contracts, Von der Leyen cites "interesting evidence" that AstraZeneca's contract with the UK was signed the day after the one it signed with the EU in August. "So that point doesn't count anymore," she said. While forgetting a little quickly more than four months of negotiations with Moderna.

Several voices have been raised in Europe to denounce this situation. The EU had ordered "too late and too little" and had been "stingy" in its negotiations with manufacturers, said Markus Söder, CDU / CSU member in Germany

On March 2, Austrian Chancellor Sebastian Kurz, deeming the whole process "too slow", announced a future partnership with Israel to speed up vaccine production. Denmark joined in as well. Hungary, the Czech Republic and Slovakia have already turned to the Russian vaccine. Budapest has added doses from China to its vaccine arsenal

The Time of Israel reported on January 12 that Israel had paid $ 23.5 per dose, a 30% premium over the price of $ 18 per dose for Moderna's vaccine. This additional payment represents, in the case of orders placed by the European Union to Moderna, nearly three billion dollars. This additional cost, obviously, is infinitely low compared to the financial and human cost of the epidemic in Europe. In November 2020, the Commission forecast a drop of 7.8% of GDP for the year as a whole. Since the start of the pandemic, Europe has counted on March 18: 584,215 recorded deaths (Source: European Center for Disease Prevention and Control, figures for the EU / EEA + Johns Hopkins University).

The challenge of mass production of vaccine doses
As of March 19: 44,274,497 doses of Pfizer / BioNTech vaccine, 16,116,000 doses of AstraZeneca vaccine; 4,154,230 doses of Moderna vaccine were administered to the European population

Anticipating future production demands in Europe for its vaccine, Moderna signed an agreement with ROVI in Spain on July 9, 2020. As part of the agreement, ROVI will provide vial filling and packaging capacity by procuring a new production line and equipment for compounding, filling, automatic visual inspection and labeling to support production of hundreds of millions of doses of the vaccine candidate intended in principle to supply markets outside of the US starting in early 2021.

In order to significantly increase production from the second quarter of 2021, Moderna signed a second agreement at the end of last December to support formulation and fill-finish a part of the Moderna COVID-19 vaccine supply outside of the US. The activity will be performed in Recipharm's drug product manufacturing facility located in France.

The ROVI industrial site in Madrid delivered the first batches of bottles last January to the Moderna store in Belgium. The Belgian site of Moderna is in charge of deliveries for Europe, UK, Switzerland, Israel, South Korea ... Rovi has implemented a production capacity in the first quarter of 2021 of 20 million doses. A second packaging line was installed in 8 months will significantly increase industrial capacity to 40 million doses per month from April 2021. A third line will be installed at the end of 2021. The industrial site will have a production capacity of over 800 million doses per year in 2022.

Recipharm will start production in the first week of April with a production capacity of more than 20 million doses per month. ROVI and Recipharm will offer Moderna a global capacity of more than 180 million doses in the second quarter of 2021. However, the bulk manufactured by Lonza at its Visp site must be available in order to achieve this objective. The same is true for packaging articles for bottles, stoppers, etc.

In the first quarter, Moderna will have delivered 10 million doses to the European community and Pfizer will have delivered more than 66 million doses from its Puurs site in Belgium. BioNTech's Marburg site with an annual production capacity of 750 million doses per year started production of doses in March. The European Commission says it will receive, in the second quarter, 200 million doses of Pfizer and 35 million doses for Moderna. This represents a fifth of Moderna's CDMO network production capacity for the second quarter. Which is relatively low. How to explain such a gap? And one can ask the question about its destinations of more than 100 million doses of Moderna vaccine for the second quarter of 2021? Are they largely destined for the UK or the US? The slow pace of negotiations with Moderna has probably had an impact on the current situation and the control command planning between Europe and other customers Moderna outside Europe

Laboratories and subcontractors have set up a complex supply chain on several continents in a very short time, just over 12 months after the first wave of contamination in Europe. European CDMOs fully contributed to this performance. After a start of vaccinations, in the first quarter, slower than expected for several European countries. The fully operational production capacities in the second quarter should allow a significant acceleration of vaccinations in Europe.

The European Commission plans to receive in the second half of the year, 200 million doses of Pfizer, 35 million two doses of the Moderna vaccine, 70 million doses are expected for the AstraZeneca vaccine. That is to say a total of 305 million doses which will make it possible to vaccinate more than 150 million people with two doses. Hopefully, more than 50 million doses of Janssen's vaccine will be added in the second quarter. As this vaccine is administered with a single dose, it will immunize 50 million additional people. Theoretically 200 million people could be vaccinated in the second quarter of 2021. In total if we cumulate the finalized vaccinations (with two doses and one dose for the Janssen vaccine) in the first and second quarter, more than 220 million theoretically will be vaccinated at the beginning of July or nearly 65% of the European population over 18 years old. The committee has not yet communicated the quantity of doses available in the third quarter.

The reasons for a too slow start in Europe
Europe, by its lack of political leadership, has fallen considerably behind in the organization of a price competition process for vaccines and has forgotten the overarching objective of accelerating effective vaccination.

The economic absurdity of such a calculation is obvious, as is its coldness in the face of daily deaths from the pandemic. Even more frightening is the impact in terms of unsaved lives. Between March 1 and March 14, over 30,000 people died from Covid in Europe.

The European Commission prioritized low-cost vaccines from the outset of negotiations by completing its first contract with AstraZeneca for the purchase of 300 million doses and an option for 100 million doses. The contract published on August 27 is based on the advance purchase agreement approved on August 14 with AstraZeneca, which will be funded by the European Commission Emergency Support Instrument. During July and August the commission announced exploratory talks with Sanofi-GSK on July 31, Johnson & Johnson on August 13, CureVac on August 18.

Agreements with laboratories using messenger RNA technology only materialized much later: November 11 for 200 million doses with the Pfizer / BioNtech vaccine and November 25 for the first 80 million doses with Moderna's vaccine.

The vaccines from Pfizer and Moderna having received their marketing authorization respectively on December 21 and January 6. Since last December, the industrial sites of these two laboratories as well as their CDMO partners have developed significant production capacities in Europe for the first industrial sites in the network. This industrial network increased its production capacity in the first quarter and will exceed nearly 200 million doses per month in April, thus meeting the challenges of vaccinating several million people.

However, AstraZeneca's vaccine hit the European market much later, only in February, after approval by the EMA on January 29. Jansen's vaccine will arrive on the market in March and that of Sanofi at the end of 2021 at best ... On the other hand, the development much more tedious than expected of the production of AstraZeneca vaccines with significant delays in deliveries impact the acceleration of vaccination campaigns in Europe.

In the United States, the FDA granted marketing authorization for Pfizer and Moderna vaccines on December 11 and December 18, respectively. The USA have mainly favored these two vaccines to start their vaccination campaigns. The availability of vaccine quantities, combined with an efficient logistics strategy for vaccine administration, has enabled the US and UK to start vaccination campaigns much more quickly.

The EU has been completely absent from the phase of identifying promising projects, funding their R&D and clinical trials. The strategy put in place by the EU would have required industrial skills that the administrators do not have. The United States implemented it as part of Operation Warp Speed. British and American leaders have anticipated and integrated into their financing and support plans from small biotechnology firms to the largest big pharma. Moderna, BioNtech and the University of Oxford Laboratory.

It is possible to hope that more than 60% of the population in Europe will be vaccinated by the end of June, beginning of July. However, the virus is still setting clocks and it is to be hoped that during the coming months that no variant of the virus will call this forecast into question.

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