IT IS LOOKING more likely every day that Ireland’s first Covid-19 vaccinations will be administered before the end of 2020.

European Commission President Ursula von Der Leyen this week announced vaccinations will begin in EU countries from 27 December. This Monday the European Medicines Agency will meet to conclude its evaluation of the Pfizer/BioNTech vaccine.

The HSE has said it expects the first delivery of the Pfizer vaccines to consist of almost 5,000 doses.

TheJournal.ie has been breaking down the latest pandemic and vaccine developments in explainers, factchecks and other articles in recent months. As well as this, we’ve started a dedicated vaccine Q&A series to help answer questions readers may have – either about a specific Covid-19 vaccine or how the programme will work in Ireland.

We’ve already covered topics like safety for pregnant women and those with underlying conditions, government indemnity, and Ireland’s cold chain resources.

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We’ve also had a number of questions from readers who drew parallels between the Covid-19 vaccines and the Swine Flu vaccine in 2009 – because of the speed at which they were developed.

• My concerns have been heightened by the terrible consequences suffered by a number of children from the speedily-developed Swine Flu vaccine a few years ago.
• What are the chances of getting narcolepsy or other serious side effects as per the previous Swine Flu vaccine?

Swine Flu is a respiratory disease that regularly causes outbreaks of influenza in pigs.

Swine Flu viruses do not usually infect humans, but there have been some rare examples of circulation in humans, the most notable of which was the 2009 pandemic. Symptoms are similar to those of the seasonal flu. 

In 2009, the A(H1N1)pdm09 influenza virus spreading in the human population contained genes from pigs, bird and human influenza viruses in a combination that had never been reported before in any part of the world. 

When the World Health Organization (WHO) declared the flu caused by H1N1 to be a pandemic, almost 30,000 confirmed cases had been reported in 74 countries. The majority of cases at that time were in people under the age of 25.

Around one third to half of the severe and fatal infections were occurring in previously healthy young and middle-aged people. 

The Pandemrix vaccine was one of the vaccines approved for use by the European Commission, on the recommendation of the European Medicines Agency (EMA) and this vaccine was used in Ireland.

There were fears of about the implications of a global pandemic and to ensure a vaccine was available as soon as possible, the European Medicines Agency allowed companies to bypass large-scale human trials.

Speaking to TheJournal.ie, Dr Lorraine Nolan, Chief Executive of the Health Products Regulatory Authority (HPRA) said the fast-track procedure used in the case of a flu is “entirely different” to the current process for the Covid-19 vaccines.

“Flu is a very well established virus. Pandemics can arise due to different strains,” she explained.

For the Swine Flu vaccine, companies could submit data for a ‘mock-up’ vaccine, rather than data from rigorous and large-scale trials. 

“It’s possible to insert the flu strain into the vaccines we already have developed. These are entirely different kinds of vaccine technologies. The flu vaccine is based on inactivated virus.

What we’re talking about in relation to Covid-19 vaccines is much more novel vaccines, [that may include] use of genetic material – not inactivated virus.

Use of the Pandemrix vaccine was suspended in Ireland in 2011. When reports emerged of children and adolescents developing narcolepsy after being given the vaccine in Ireland, a National Narcolepsy Steering Committee was established to investigate a potential link.

The committee’s report in 2012 found that there was “a significant 13-fold higher risk of narcolepsy in vaccinated compared to unvaccinated individuals”.

As part of its agreement to secure the vaccine, the government in Ireland had agreed to indemnify the developer GlaxoSmithKline. There are around 80 legal actions being taken in Ireland over the Pandemrix vaccine.

Just last month a 15-year-old boy who was diagnosed with narcolepsy after receiving the vaccination at school in 2010 settled his case against the HSE, the Minister for Health and the pharmaceutical company. 

The British Medical Journal published an investigation last September which noted that serious safety concerns were raised in 2009, nearly two years before the vaccine’s use was stopped in Ireland.

A study by a team from the United Kingdom’s Health Protection Agency (HPA) and two hospitals, also published in the BMJ, suggested that the risk of narcolepsy in children aged 4 to 18 after receiving Pandemrix was about 1 in 55,000 doses.

Regulation of Covid-19 vaccines

While it is true to say that the timescale from start to finish for Covid-19 vaccines has also been significantly reduced, the reasons this time are different.

The usual barriers for scientific research and development, such as financing, were not there with this disease because of the scale and impact of this pandemic.

There was an intense focus from a large number of research groups across several countries, with the backing of governments and global institutions.

None of the vaccine developers have been able to submit data for a ‘mock-up vaccine’ or skip any of the usual trial phases for Covid-19 vaccines. The vaccine candidates have all had to go through the normal trial process.

In pre-clinical trials, an experimental vaccine is first tested in animals to evaluate its safety and potential to prevent disease. Then the developer will move to clinical trials, with three phases to work through before they apply for approval.

In Phase 1, the vaccine is given to a small number of people to assess safety for human use, to confirm it generates an immune response and to test dosage levels.

In Phase 2, the vaccine is given to hundreds of people. They are monitored for any side effects – mainly the more common side effects would be picked up at this stage.

At this stage developers also collect data on the efficacy of the vaccine in preventing disease, but numbers are too small for a clear picture. A proportion of the volunteers in this phase will receive a placebo or in some cases another vaccination. This is known as a control group – it allows researchers to make comparisons between those who receive the vaccine and those who do not. 

In Phase 3, the vaccine is given to thousands, or tens of thousands of volunteers. Again, there will be control groups and a proportion will receive a placebo so data from the groups can be compared. This phase gives a clearer picture of how effective the vaccine is in eliciting an immune response and the appropriate dosage.

With a large – and more diverse – pool of volunteers, this phase also aims to catch less common side effects and examine the prevalence of side effects overall.

Once the results of these clinical trials are available, reviews of efficacy, safety and manufacturing are carried out before approval by regulatory authorities.

What has changed in the regulatory process is that the European Medicines Agency (EMA) has been doing ‘rolling reviews’ of the data coming out of the trials. This means they did not wait until they were fully complete to look at everything, they have been monitoring them as they progressed.

When the vaccine development is progressed enough for a ‘marketing authorisation application’, the formal assessment procedure can take place in a shorter than usual timeframe, because the data has already been scrutinised during the rolling review.

The Committee for Medicinal Products for Human Use (CHMP) is responsible for preparing the agency’s opinions on questions concerning medicines, including vaccines.

Dr Nolan said the HPRA and other national regulatory authorities for individual member states are involved in the entire process.

When a marketing authorisation application is submitted, all member states who are members of this committee can see the data and two member states prepare reports. But we all get the opportunity to review the data and comment on reports to come to a collective decision. It’s a phenomenal pool of experts that’s being used.

If comprehensive data is not be available at the time of the marketing authorisation application, the EU regulatory system is designed to potentially accommodate this situation by providing for a ‘conditional authorisation system’.

The EMA says this means that the initial (‘conditional’) authorisation granted by the Commission is “based on less comprehensive data than would normally be the case (nonetheless with a positive benefit-risk balance), and with obligations on the developers for the data to be completed afterwards and to be submitted for assessment”.

Side effects in trials

Dr Fidelma Fitzpatrick, consultant and senior lecturer in microbiology at the Royal College of Surgeons (RCSI) said because of the severe impact of Covid-19 and because it was completely new, the entire world has been focused on it.

She said one of the main reasons it usually takes so long to develop a vaccine is “because of the red tape”.

Scientists in the college spend a lot of time writing grant applications looking for money to fund their research. Part of the speed of this is that the scientists didn’t have to go looking for money, funding was put in place straight away and they were allowed to just focus on one thing.

However she said the speed does not mean developers will be given a free pass when it comes to the regulatory process.

“The regulators have been looking at the data all the way through, I’ve never seen such scrutiny. A lot of the data is also publicly available, which is great.”

Although the full data from the main vaccine candidates has not yet been made publicly available and no vaccines have been approved for use in the European Union so far, there are strong positive indications in terms of efficacy and safety.

The Pfizer vaccine, which is expected to be approved for use in the EU before the end of the year, has also already been approved in Britain, the US, Canada and Singapore. 

“When people query safety it’s important to have facts rather than opinions. There are two things in particular that have been published that are publicly available and anybody can look at them and read them themselves,” Dr Fitzpatrick said.

“One is a paper from the Oxford group published in The Lancet – with an accompanying editorial and a podcast – the other is an FDA document with details and analysis of the Pfizer vaccine.

The Lancet paper is the first peer reviewed paper at that stage, when it’s sent to a journal it is sent out for blind review and a number of external experts will review it. It’s a pretty rigorous process. This is the first peer reviewed evidence that the vaccine can stimulate an immune response that protects against severe Covid.

According to this paper, there were 175 serious adverse events in the trials, out of 23,745 participants, but just three were possibly related to the study.

One of these was a case of transverse myelitis, [inflammation of a section of the spinal cord] in a participant who was receiving the vaccination. Their adverse event occurred 14 days after their booster dose.

Another adverse event possibly linked to the trial was a case of haemolytic anaemia [a blood disorder]. This participant was in a control group [see definition above] so they received either a meningococcal conjugate vaccine or saline. They did not receive the Covid-19 vaccination at all. 

The third adverse event was a participant who had a fever higher than 40 degrees. This participant is in a ‘masked’ group, which means researchers do not yet know whether they received the placebo or the Covid-19 vaccine. 

There were two other cases of transverse myelitis, but these were not believed to be connected to anything that was done in the trials. One was attributed to pre-existing multiple sclerosis and the second was in a control group – in which people were not given the Covid-19 vaccine. Researchers in the trial have said all participants have recovered or are recovering.

According to the FDA document on Pfizer’s Phase 3 trial of 38,000 people, there were four cases of Bell’s palsy [a condition that cases temporary weakness or paralysis in the facial muscles] in the vaccine group.

However the FDA said this does not represent a frequency above that expected in the general population. The frequency of serious adverse events was less than 0.5%, without meaningful imbalances between the vaccine group and the placebo group. 

“For me the bottom line is that from these two vaccines it doesn’t seem at this stage that there is any huge signal of a major side effect,” Dr Fitzpatrick said. “Bear in mine these are interim analyses, there are more people to study and follow-up on.”

She said the majority of the side effects reported from trials so far are the usual temporary short-term effects such as redness or soreness around the injection site.

“People who get the flu vaccine each year will be familiar with it, you might have a bit of a sore arm for the day after you get it.”

‘Good safety profile’

The HPRA’s Professor Nolan said while decisions still have to be made by the EMA, the vaccine candidates “seem to have a really good safety profile”.

“We can expect them to have the typical profile [of side effects] such as site reaction, headache, fever or chills. These are things we expect from vaccines and they pass within 24 hours.”

Nolan said if European regulators had any concerns about the safety of the vaccines, they would not make them available. She said the majority of side effects are generally seen within four to six weeks after the vaccination has been administered and there is a significant amount of data from the trials to indicate levels of adverse incidents within this timeframe. 

She said the risk versus benefit has to be weighed up with all vaccines – and that it’s becoming clear that the benefits here far outweigh the risk.

When we move from a situation where we have clinical trials with tens of thousands of participants and then move into real world use with millions and billions in this case, it is possible very rare side effects will show up – but it’s only possible. What I will say is that it’s probably less than a one in 100,000 probability.

“When you balance that against the known risk of Covid-19, one in 40 people that have got this globally died and 8% of people in Ireland who had it were hospitalised with it. Out of 100,000 people that would be 8,000 people in hospital. The known risk of Covid-19 far outweighs any risks from a vaccination.”