DUBLIN – Amid a bitter dispute between the European Commission (EC) and Astrazeneca plc over supplies of the latter firm’s SARS-CoV-2 vaccine, the EC’s drug regulator, the EMA, recommended approval of the product in question, COVID-19 Vaccine Astrazeneca (formerly AZD-1222).

The EMA’s Committee on Human Medicinal Products (CHMP), which conducted the appraisal, followed the lead of its U.K. counterpart, the Medicines and Healthcare Products Regulatory Agency (MHRA), in recommending the vaccine for all adults ages 18 and older. Its recommended schedule is a two-dose regimen to be administered at a four- to 12-week interval.

The CHMP’s appraisal of the vaccine’s effectiveness was more stringent than that of the MHRA, however. Based on its assessment of the data, the vaccine had a 59.5% efficacy rate in preventing symptomatic COVID-19.

Of the four clinical trials Astrazeneca included in its application, the CHMP only included two in its efficacy analysis, the COV002 and the COV003 studies, conducted in the U.K. and Brazil, respectively. The MHRA followed the same course. The event rates in the other two studies, COV001 and COV005, conducted in the U.K. and South Africa, respectively, were too low to permit a proper efficacy evaluation – less than five cases occurred in each.

Unlike the MHRA, however, the CHMP excluded from its efficacy analysis any data derived from protocol deviations, which led to a pool of trial participants receiving half of the standard dose, followed by the standard dose. Astrazeneca claimed that regimen actually boosted the efficacy of the vaccine to 90%. The CHMP did consider whether it should include those data in the analysis. “That was extensively discussed,” Bruno Sepodes, vice chairman of the CHMP, told reporters during an EMA press briefing. However, there were “so many confounders,” so they ultimately decided to exclude those data.

Germany’s Standing Committee on Vaccination (SITKO), which is convened by the Robert Koch Institute, had, unusually, anticipated the CHMP recommendation, by stipulating it would recommend limiting the vaccine to adults under the age of 65, in guidance published on Jan. 28. The SITKO concluded that there is insufficient evidence to support the vaccine’s effectiveness in the older population, because the clinical trials on which the approval is based recruited very low numbers of older participants.

The apparent divergence does not appear to be an issue. “The reason we are still recommending [its] use in this age group is that, based on the immunogenicity data that was available for this age group and on the experience we got from the previous vaccines, at least some protection is expected in this subgroup, although the exact level of protection cannot be estimated for the time being,” Sepodes said. The recommendation is not, therefore, at odds with the SITKO position. “It can be used. If there are other options, those could be preferred in specific situations.” Further evidence in support of the vaccine’s efficacy in older people could come from a U.S. phase III trial in 30,000 volunteers. Data are expected toward the end of March.

‘Best reasonable efforts’

The scientific appraisal of the vaccine is a wholly separate issue from the unresolved political row accompanying its rollout, but in the current diplomatic atmosphere, which has already been badly soured by Brexit, the positive outcome of that process does nothing to soothe the antagonism between Brussels and Cambridge, U.K.-based Astrazeneca.

Ursula von der Leyen, president, European Commission

EC President Ursula von der Leyen and Astrazeneca CEO Pascal Soriot publicly stuck to their mutually irreconcilable positions over the past week. Von der Leyen maintains that Astrazeneca is contractually required to supply 80 million doses during the present quarter, whereas Soriot claims that the company he leads is only obliged to fulfill the purchase agreement on a “best reasonable efforts” basis. Manufacturing problems at its Belgian plant will now limit its shipments to the EU to 31 million doses in the first quarter, whereas its U.K. shipments are unaffected.

Astrazeneca is, obviously, unable to summon up vaccine doses that do not exist. At the same time, it is not clear why shipments to the U.K. are shielded from the wider problems within the company. Astrazeneca’s separate supply contracts with the U.K. and the EC do not appear to have been explicitly tied to particular production plants.

Pascal Soriot, CEO, Astrazeneca

Soriot maintained, in an interview with an Italian newspaper, that because it moved earlier in striking a deal, the U.K. was entitled to preferential treatment. The EC’s health commissioner, Stella Kyriakides, brutally dismissed “the logic of first come, first served” earlier this week: “That may work at the neighborhood butchers, but not in contracts. And not in our advance purchase agreements. There's no priority clause in the advance purchase agreement. And there's also no hierarchy of the four production plants named in the advance purchase agreement. Two are located in the EU and two are located in U.K.”

The legal niceties of the present dispute are difficult to unravel. Although the EC published its contract with Astrazeneca Jan. 29, it did so in a heavily redacted form, so many of the key clauses are not legible. The term “best reasonable efforts” appears 15 times in the text, however, which suggests that Astrazeneca has some room for legal maneuvering. At the same time, Astrazeneca stated in the contract that “it is not under any obligation, contractual or otherwise, to any person or third party in respect of the initial Europe doses or that conflicts with or is inconsistent in any material respect with the terms of this agreement or that would impede the complete fulfilment of its obligations under this agreement.”

Astrazeneca officials, although they may have overpromised, might feel entitled to feel aggrieved at being embroiled in a damaging dispute, given that the company is supplying its low-cost vector vaccine, based on a replication defective chimpanzee adenovirus, on a not-for-profit basis. But the EC has proceeded to put in place a targeted “transparency and authorization mechanism” under which individual member states could block the ex-EU shipment of certain COVID-19 vaccines made within their territories. The measure is limited to vaccines that are subject to advance purchase agreements with the EC. It is also time limited – it applies to the end of March 2021 only. But between now and then, affected companies are required to seek authorizations before they can export COVID-19 vaccines. It will not affect the EU’s existing humanitarian aid commitments or its support of the COVAX facility, which is intended to secure COVID-19 vaccine supplies for low-income countries and other countries that have not closed bilateral deals with vaccine producers.

The European Federation of Pharmaceutical Industry Associations, a Brussels-based industry lobby group, said any export restrictions would “undermine the supply of vaccines in Europe and around the world” and could compound the present impasse. “Risking retaliatory measures from other regions at this crucial moment in the fight against COVID-19 is not in anyone's best interest,” it stated.

More vaccines coming

The zero-sum game of Brexit politics constitutes an additional ingredient in this whole affair. The U.K. government was initially criticized for deciding on a go-it-alone strategy, having declined an invitation to participate in the EC’s large-scale procurement initiative. But the strategy devised and implemented by its Vaccine Task Force, led by venture capital veteran Kate Bingham (who was succeeded at the start of this year by another industry veteran, Clive Dix) is looking increasingly successful. The U.K. placed its bets early and widely, adopting a portfolio approach to building a vaccines pipeline. Its immunization campaign is well ahead of efforts in other European countries.

The EC, representing the needs of 27 member states, moved more slowly, although both regions have, inevitably, converged on the best-in-class vaccines that offer significant levels of efficacy. The encouraging phase III trial data disclosed Jan. 29 by Johnson & Johnson, of New Brunswick, N.J., and late Jan. 28 by Novavax Inc., of Gaithersburg, Md., will not alleviate the present supply shortages, but both should broaden the available options in the coming months. (See European Commission and U.K. SARS-CoV-2 vaccine purchase agreements, below.)