Covid-19 vaccine: How do they work and are they safe?

It comes after Pfizer and BioNTech released interim results of their Covid-19 vaccine trial. Although it is not the only vaccine in the late stages of testing, the large size and careful design of the trial, not to mention the promising results, have caused understandable enthusiasm around the world.

As we get nearer the long-awaited start of a Covid-19 vaccine roll-out across the UK, it is worth looking at how statisticians help medics establish the safety of vaccines.

Professor Adam Kleczkowski from the University of Strathclyde has debunked the myths...

How effective is the vaccine?

It is not easy to find out how effective a vaccine is. First, researchers need to know whether just an act of injecting somebody can help.

The trials involve a large number of people, with half of them given a vaccine and the other half a placebo.

Then the participants need to be exposed to the infection with the expectation that most of those in the control group become ill, but vaccination protects at least some in the treated group.

In some cases, such as for HIV or Ebola, even giving a placebo can be ethically controversial as they have such a high death rate.

For coronavirus, the researchers need to rely on natural infection because no study, at the moment, intentionally exposes participants to the coronavirus. As a result, the efficacy calculation is based on a relatively small number of those who caught COVID-19 by contact with other infected people.

Vaccine efficacy reflects a proportion of the number of those who became ill in the vaccinated group and in the non-vaccinated group.

The Pfizer/BioNTech trial involved nearly 44,000 participants, with 21,999 given the vaccine.

The researchers use statistical analysis to set up milestones at which they can be increasingly confident that the vaccine works – or it does not – as the cases trickle in.

If the numbers are small, it would not be clear whether the difference in the outcomes between the placebo and the treated groups is real or just a result of a random fluke.

Statisticians use the so-called “power analysis” to discover how many cases we need to observe. For the Pfizer and BioNTech vaccine, the target was 164 cases when the final estimation of efficacy can be made, but this was based on the assumption that the vaccine is only 60% effective.

This was based on the seasonal flu vaccine efficacy. However, with the numbers exceeding expectations, the company decided to release the results at one of the interim analysis points.

Ninety-four cases were reported and the split of about 86 cases in the placebo group and eight cases among vaccinated yielded 90% efficacy. This level of protection against infection is remarkable.

Even though the study is based on a relatively small number of cases, statistical analysis allows the researchers to extrapolate to what might happen when the vaccine is rolled out.

The trial included different ages as well as people from different ethnic minority groups, but more studies would be needed to assess how the most vulnerable groups are protected.

The final efficacy is likely to be lower, as administering the treatment is difficult for many logistical reasons, including the requirement of mRNA-based vaccines, of which the Pfizer vaccine is one, to be stored at very low temperatures. In the real world, the vaccine might not be stored at the correct temperature and hence may spoil.

How safe is the vaccine?

If the vaccine is to be widely applied, the medical community and the public need to be reassured about its safety.

The Pfizer vaccine was administered to 21,999 people. Some people reported a reaction similar to the one after the seasonal flu vaccination, but so far no serious side-effects have been reported. But how can we be sure that this holds if the treatment is rolled out to millions of people?

Statisticians came up with the “rule of three”. The rule tells us that if 21,999 participants were treated with no side-effects, then with 95% confidence, the probability of a side-effect from the vaccine is expected to be less than three (hence the name) divided by 21,999 and so less than one in 10,000.

The chance of these side-effects is probably even lower, but the researchers will be keen to extend the trials further to confirm this.

Safety is just as important as efficacy. If you take a probability of one in 10,000 and extrapolate that out to the 300 million population slated for vaccination in the US alone, the number of people with side effects could be as high as 30,000.

Clearly, the doctors need to ensure they are not causing harm, but also any serious side-effect attributable to the vaccine would damage the reputation and significantly affect the take-up.

How to use the vaccine so it is effective and safe?

Medical authorities are now designing ways to implement vaccination in nationwide programmes, but the details on how to do this depend on several factors.

The UK government has ordered 40 million doses of the Pfizer vaccine which – with two-dose treatment – would vaccinate 20 million people, that is, everyone aged 55 and up. However, the roll-out will not be fast since production and delivery will take time.

The strategy also depends on what the vaccination programme is supposed to achieve. Childhood vaccines, such as measles, are given to newborns to maintain herd immunity. In this case, only a relatively small proportion of the population needs to be vaccinated. With the rapid spread of COVID-19 – and high levels of existing infection – the proportion would need to be much higher.

Predictions for the level of immunity required to reach herd immunity depend on our estimate of the COVID-19 basic reproductive number, R.

In absence of any control measures, R is estimated to be around 3 and so at least 67% of the public need to be fully immune just for the epidemic to stop growing. Higher values would need to be achieved if the aim is to eradicate the virus.

This level will hardly be achievable with 60% efficacy, even if the whole population is vaccinated.

The value of R=3 assumes the return to the behaviour before the pandemic. If we keep some level of restrictions and use masks, R could be lower and the herd immunity easier to achieve.

On the positive side, our simple models might be too pessimistic about the herd immunity levels. Additionally, if perhaps as many as 20% of the public already have had COVID-19, the required level of vaccination might be much easier to achieve.

Alternatively, vaccination can be applied to these segments of the society who are either at high risk of infection (healthcare and care home workers) or high risk of death (vulnerable, care home residents). This is the recommended strategy in the UK.

Are we there yet?

The results of the Pfizer vaccine trial are highly promising. But the road to eradicating the coronavirus is likely to be long and difficult. Besides establishing the potential for the vaccine to protect against the virus, we also need to know whether it gives a lasting immunity or whether it would need to be applied repeatedly, for example, as with tetanus or seasonal flu vaccines.

But the policymakers and researchers also need to balance the requirement for stopping the pandemic with the fears of side-effects and the resulting vaccine hesitancy. While it is easy to dismiss these concerns, they need to be taken seriously if the vaccination is to be successful.

What has the PM said about the vaccine?

Boris Johnson has said everyone who is eligible should “definitely” get a coronavirus vaccine as the official UK death toll from the disease passed 50,000.

The Prime Minister said he would have “no inhibitions” about getting a vaccine himself as he dismissed the arguments of the so-called anti-vaxxers as “total nonsense”.

It came after Professor Jonathan Van-Tam, the deputy chief medical officer for England, said they were preparing for the most important vaccination programme “in decades” – a reference to the news that a vaccine being developed by Pfizer-BioNTech had proved 90% effective.

During a visit to a supermarket distribution centre in south-east London, the Prime Minister said that once a vaccine was cleared for use, it was essential to ensure there was as wide a take-up as possible.

“I have got no inhibitions about getting a vaccine,” he told reporters.

“Certainly I would say to everybody anti-vaxx is total nonsense – you should definitely get a vaccine.”

The call appears to reflect concerns among officials that misinformation by anti-vaxxers could deter some people from getting the vaccine.

At a Downing Street press conference on Wednesday (November 11), Prof Van-Tam said he had advised his own mother that she should get it.

“If I could be at the front of the queue, then I would be. I think the ‘mum test’ is very important here,” he said.

“My mum is 78 – she will be 79 shortly – and I have already said to her: ‘Mum, make sure when you are called you are ready. Be ready to take this up. This is really important for you because of your age’.”

The appeal came as the latest Government data showed 50,365 people had died in the UK within 28 days of testing positive for Covid-19 – making it the first country in Europe to pass 50,000 deaths. However, other statistics suggest the true figure for coronavirus deaths could be more than 65,000.

Labour leader Sir Keir Starmer said it was another “grim milestone” in the pandemic, accusing the Government of again being too slow to act as it entered the latest phase.

“We owe it to all of the families who are grieving to get on top of the virus and head towards a vaccine and that’s what the Government must absolutely focus on now,” he said.

Mr Johnson said every death from the disease was a tragedy and that while the prospects of a vaccine and mass testing offered hope, it was essential people continued to observe social-distancing rules.

“We have two boxing gloves to pummel the disease in the weeks and months that follow,” he said.

“But I have got to stress that we are not out of the woods yet. It does require everybody to follow the guidance.”

Ministers have said they do not expect the mass roll-out of a vaccine to begin until next year.

Downing Street said that it would not be made available until the regulator, the Medicines and Healthcare products Regulatory Agency (MHRA), was satisfied that it was safe.

“Any vaccines which are determined for use will undergo a vigorous series of safety checks, they will be absolutely safe for the public to use,” the Prime Minister’s official spokesman said.

Dr June Raine, the MHRA chief executive, said there was “absolutely no chance” it would compromise on standards of safety or effectiveness when it came to a coronavirus vaccine.

Prof Van-Tam said a vaccination programme would target those groups at the highest risk from the disease first.

With ministers warning it will require a “colossal” effort by the NHS, supported by the armed forces, he said he would be willing to pitch in and help administer jabs himself.

“This is one of the most important, if not the most important, vaccination programme we’ve done for decades,” he said.

“And from that perspective, I don’t mind telling you, I’ve had the conversation at home.

“If I can help with this in some evenings and weekends, doing some extra vaccination sessions myself, then I’m going to.

“That’s a given if I can get on the list and be useful.”

Will things go back to normal by Easter 2021?

Prof Van-Tam would not be drawn on whether lives would be back to normal by Easter, saying it was not yet clear if the vaccine prevented onward transmission of the virus or simply stopped individuals falling ill.

But he added: “I think I can tell you that I’m very hopeful that, over time, vaccines will make a very important difference to how we have to live with Covid-19 in the long run.”

• Parts of this article have been republished from The Conversation under a Creative Commons license.