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Donald Macarthur and Dr. Meriem Bouslouk-Marx discuss post-approval findings of national committees in Europe charged with deciding the best strategy to use a new COVID-19 vaccine in their populations.
By end-January 2021, three COVID-19 vaccines had received conditional marketing authorizations (valid one year) by the European Commission, covering all EU-27 countries, following a positive opinion from the European Medicines Agency (EMA). Each vaccine also received emergency-use authorization post-Brexit from the UK regulator, the Medicines and Healthcare products Regulatory Agency (MHRA).
There are two to three market access steps for a vaccine which can run in sequence (usually) or in parallel (especially in an emergency): (1) regulatory approval based on best estimates of clinical and CMC data, (2) population target recommendation based on models and population acceptability, and (3) cost effectiveness assessment and price negotiation. Depending on the country, steps (1) and (3) may be combined.
This article discusses post-approval findings of national committees charged with deciding the best strategy to use a new vaccine in their populations, with special reference to the Oxford/AstraZeneca (AZ) vaccine. This was the first to have Phase III results published in a peer-reviewed journal and attracted the greatest controversy. It will not address the associated EU vaccine procurement debacle.
Though issues around usage of the AZ vaccine in older adults were expressed since release of the first trial results in the The Lancet on December 8, 2020, the drama really kicked off for the wider public on January 29, 2021. Speaking at a press briefing a few hours before the EMA issued its opinion on the AZ product, French President Emmanuel Macron said this vaccine was ”quasi-ineffective” in people over the age of 65 years. The over-65 age group is the one in which the overwhelming number of serious illnesses, hospitalizations and deaths from COVID-19 occur, so the implication was clear. The vaccine did not work well in those most at risk. Mr. Macron also criticized the UK’s decision to give doses 12 weeks apart, claiming this could ‘accelerate the mutation’ of the virus.
No data were provided by Mr. Macron and he had no experts at his side. France’s National Authority on Health (HAS) was yet to reach its conclusion. Some believe the remarks reflect the President’s well-known dislike for Brexit (AZ is a UK-headquartered Anglo-Swedish company) allied to frustration over slow COVID-19 vaccine developments in the country of birth of Louis Pasteur. Sanofi (the largest vaccine producer in Europe) has pushed back its vaccine release date to end-2021 and Institut Pasteur has abandoned its first programmed entirely. Others thought the President was trying to dampen demand due to vaccine shortages. But where had he obtained the information to support his views? Eyes turned towards another member state with negative views on Brexit, Germany, where there had been several developments over the preceding few days.
A surprising article, attributed to an anonymous source within the government’s ruling coalition, appeared on January 25, 2020 in both Handelsblatt, Germany’s business daily, and mass circulation Bild. The AZ vaccine had only 8% efficacy in over-65s against COVID-19 they said (i.e. were 100 unvaccinated elderly people to get the virus, 92 vaccinated would too), rendering it next to useless in the most vulnerable group. No explanation or data were provided, on the basis it was a ”political story.” Within hours denials came from all quarters and the Federal Ministry of Health (BMG) said the 8% figure may be a misreading of the trial results: 8% of participants were in the 56-69 age bracket (and only 3–4% over 70 years of age). Handelsblatt doubled down on its story in the following day’s edition, though this time it quoted a high official of the BMG, claiming the available data showed less than 10% efficacy in the over-60s (not over 65s).
On January 28, the BMG released draft recommendations from Germany’s Standing Committee on Vaccination (STIKO), marked confidential and dated January 26. ”Currently, no sufficient data is available to assess the effectiveness in over-65s,” it said. The draft recommended not using the vaccine in this age group. It also included a calculation showing 6.3% efficacy in over-65s that might have led to Handelsblatt’s claim. This was based on just two infections — one in the intervention arm, one in the control arm — and, coming with a huge 95% confidence interval of -1405 to +94.2 rendered it meaningless.
Just ahead of the EMA recommendation on January 29 for a conditional marketing authorization, German Health Minister Jens Spahn said, ”We do not expect an unrestrained authorization.” In the event, the EMA, like the MHRA, did not impose any upper age restriction on the AZ vaccine. As the EU Agency explained:
”Most of the participants in these studies were between 18 and 55 years old. There are not yet enough results in older participants (over 55 years old) to provide a figure for how well the vaccine will work in this group. However, protection is expected, given that an immune response is seen in this age group and based on experience with other vaccines; as there is reliable information on safety in this population, EMA’s scientific experts considered that the vaccine can be used in older adults. More information is expected from ongoing studies, which include a higher proportion of elderly participants.”
AZ CEO Pascal Soriot, in an interview with Italy’s La Repubblica, explained his research team started vaccinating older people later so it did not have ”a huge number of older people who had been vaccinated…but we have strong data showing very strong antibody production against the virus in the elderly, similar to what we see in younger people.” He added that it was possible some countries might use the vaccine just for younger people ”out of caution.”
A new Coronavirus Vaccine Ordinance was issued on February 8th by Germany’s BMG saying that if STIKO recommends vaccines are used exclusively for persons aged over 18 years and up to 65 years, ‘these persons should primarily be supplied with the vaccines’.
Like Germany, several other EU and non-EU European countries reached different conclusions to the EMA:
HAS recommended that until new data are available on the AZ vaccine, mRNA vaccines should be employed in over-65s. For now the AZ product should be used in healthcare workers under 65 and for people aged 50-64 with comorbidities.
The Interministerial Conference (CIM) approved the Task Force recommendation. The AZ vaccine should primarily be used in the age group 18 to 55 for healthcare professionals, people with comorbidities (except immunodeficiency) and the police.
mRNA vaccines are preferred for use in the oldest and most fragile members of society, the Italian MedicinesAgency (AIFA)’s Scientific-Technical Committee said. The AZ vaccine is currently preferred for people aged 18-55 because evidence for this group is firmer.
The maximum age to receive the AZ vaccine is 55 years, according to the Public Health Commission.
Use of AZ vaccine is preferably limited to people younger than 65 without the risk of serious COVID-19 consequences, the Danish Health Authority said.
Pfizer and Moderna vaccines should primarily be offered to the over-65s, the Public Health Agency of Sweden (FoHM) said.
Swissmedic, the Swiss Agency for Therapeutic Products, postponed consideration of the marketing authorization of the AZ vaccine because its advisory committee of external experts HMEC concluded that available data did not permit a positive risk-benefit assessment yet.
Following a recommendation of the Medical Council, the AZ vaccine should be limited to 18-60 year olds.
Following the recommendation of the Austrian National Vaccination Board, the AZ vaccine is only advised for ages 18–64.
There are insufficient data with the AZ vaccine on over-65s, the Norwegian Institute of Public Health (FHI) said.
Safety or economic concerns were not raised by any country.
Setting age limits for vaccines is not unusual. In Europe, all adult vaccines except those related to travel, occupation or underlying condition are recommended for specific age cohorts. Merck & Co’s shingles vaccine, for example, was recommended in many countries for restricted age groups because its efficacy was significantly reduced in those over 70 and also to limit public spend. Another example is with seasonal influenza programmed.
A general rule among regulators is that you cannot bridge efficacy trials to older populations with immunogenicity trials. This is because a senescent immune system responds less well to vaccines on a number of parameters, overall neutralizing antibodies being only one of these. The specificity of the antibodies and possibly the cellular immune response may be quite important, especially given the risk of adverse reaction that has been documented with other coronaviruses and modelled in COVID-19 convalescent sera. Some experts might have seen a risk with the AZ vaccine and preferred to err on the side of caution.
Advantages of the AZ vaccine are undeniable. Being offered worldwide by AZ at cost ($2-3/dose) for the duration of the pandemic and in perpetuity to low- and middle-income countries, it is cheaper for national authorities. It can also be stored under standard cold chain conditions (2-8°C) whereas the Pfizer product requires -90°C to -60°C and has a use-by date of less than one week. The Moderna vaccine requires storage at -25°C to -15°C long-term. Such temperatures present storage and distribution challenges which may limit vaccination of the housebound or those in care homes, use in small medical clinics or pharmacies, and also in countries with the lowest incomes. It should be noted, however, that Ebola vaccine needs ultra-cold storage too but was used in some African nations.
After clean water, it is generally accepted that vaccination is the most effective public health intervention in the world. Anti-vaxxers and vaccine hesitancy are real problems –the latter nowhere more so than in France (see table below). Public remarks by influential people, such as senior politicians or journalists which include the words ”vaccine” and ”ineffective” in the same sentence without evidence are to be depreciated.
Percent share of respondents who would accept a COVID-19 vaccine if it was available to them at time of survey (January 14, 2021)
Some say the UK was too quick off the mark with approval and vaccine use but delay costs lives and the country has already lost more of these to COVID-19 on a population basis than any other in Europe. The different conclusions reached by the EMA/MHRA and various national bodies on the same dataset do seem remarkable. Perhaps it reflects different cultures: Evidence-based zealotry versus pragmatism? The influence of politics on the science cannot unfortunately be ignored too. Routine vaccine recommendations generally vary between countries and sometime between regions of the same country (e.g. Italy). Decisions on which vaccine to use and which priority groups to target are also taken by buyers according to the contracts they have chosen with the producers.
Evidence on the AZ vaccine continues to flow in. There have been ongoing trials, new trials, real world vaccine effectiveness studies, new dosing, new combinations of doses, and new and modified vaccines.
Post-approval studies on the AZ vaccine, which admittedly have yet to be peer-reviewed, show prevention of hospitalization and prevention of two-thirds of onward infection, both after a single dose. On the downside, another study showed ”limited efficacy” in protecting against mild/moderate disease caused by the South African variant. Most recently, on February 10, WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) recommended it in adults ”without an upper age limit,” adding it was likely to be effective against severe illness caused by mutant strains. WHO also said the two doses should ideally be spaced by between eight and 12 weeks, with the longer gap ”associated with greater vaccine efficacy,” thus supporting the UK’s dosing strategy.