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Covid-19 vaccines: Discussing how they work, the second dose and timing with Babraham Institute immunologist




Vaccination offers by far the best – perhaps only – route out of the Covid-19 crisis.

And, with two vaccines now being rolled out in the UK and a third available in the spring, progress is being made on delivering this vital protection.

A Covid-19 vaccine
A Covid-19 vaccine

Recently, those over the age of 70 began to be contacted to make their vaccination appointments, representing the next stage of the roll-out, which began with those over the age of 80, care homes residents and staff and frontline health workers.

The majority of people will welcome the opportunity to be vaccinated against a virus that has now claimed more than 100,000 lives in the UK alone.

Yet there remain some individuals concerned about vaccine safety, or with questions about the speed of the development of the Covid-19 jabs.

Others have challenged the UK government’s decision to prioritise first doses and delay the second for up to 12 weeks.

Explaining how vaccines work, and their power to protect, can help dispel myths and ensure that as many people as possible turn up for their jabs – a vital component in providing population-wide protection.

Immunologist Prof Adrian Liston, at the Babraham Institute, tells the Cambridge Independent: “Vaccines all work in a fairly similar way. The key outcome we want are antibodies that bind the infecting virus and either block its entry to cells or flag it for destruction.

“These antibodies are made by B cells. We have a huge number of B cells in the body – roughly 10 billion – each of which has the potential to make a different antibody.

“The problem is that very few will be useful for any individual infection. Let’s say that there are around 50 B cells in the body that are good at making SARS-CoV-2 antibodies. During an infection there is a delay before these 50 B cells notice the infection.

“They then start to proliferate and make antibodies, a process which takes two weeks to really get going. What a vaccine does is simulates the infection in advance.

Prof Adrian Liston, of the Babraham Institute
Prof Adrian Liston, of the Babraham Institute

“It increases the number of useful B cells from about 50 to millions, and starts the production of antibodies. That way when you get the real infection, your immune system has a head-start and can usually shut-down the infection before you get sick.”

Due to the time taken for the production of antibodies, vaccines typically take around two weeks to deliver a protective effect.

We also know that the immune response of older people is weaker.

“Some excellent research by Dr Michelle Linterman at the Babraham Institute has demonstrated that the expansion is weaker and lower quality in older mice and people,” says Prof Liston.

And, as the Cambridge Independent recently reported, a study led by Dr Linterman showed this was the case for the Oxford University/AstraZeneca vaccine in mice. It is thought to be the case in humans too, so the study underscored the importance of the second, top-up dose.

“There is nothing especially different to the second dose,” notes Prof Liston. “It boosts up the number of B cells again, boosting up the antibody production.”

So why do some vaccines – like those against the SARS-CoV-2 virus that causes Covid-19 – feature two doses, and some involve only one?

“One of the unusual aspects of vaccine development is that they are extremely safe and extremely effective,” replies Prof Liston.

How the Oxford University / AstraZeneca vaccine works
How the Oxford University / AstraZeneca vaccine works

“For most medicines there are a lot of trials to try to hit to the optimal dose and treatment schedule, and to try to optimise the cost/benefit ratio.

“For vaccines, a good vaccine will have a large therapeutic range, work in almost everyone and have almost no cost. So quite often the time-points/dosing schedule that is first trialled works, and you just keep going with this rather than playing around.

“So when the recommendation is that tetanus vaccine is boosted every 10 years, that isn’t to say 10 years is the cut-off. Maybe every 20 years would be sufficient – it just isn’t worth doing a clinical trial to find out when we have a schedule that works so well.

“The long answer to the question about vaccine dose timing is that we usually stick with what works, because there is no real advantage to tinkering any further.

“The short answer is that usually we are focused on vaccinating kids, who tend to respond well. Vaccinating older people tends to be more difficult, so for Covid a booster is probably more important than childhood vaccines.”

Initially, the two doses of Covid-19 vaccines were going to be offered three or four weeks apart. But the government, advised by the Joint Committee on Vaccination and Immunisation, is now prioritising first doses, and the second jab of either of the approved vaccines is now administered up to 12 weeks after the first.

That does mean those given the first jab will have to wait a little longer for the fuller protection offered by the booster dose. But will it affect the vaccine’s efficacy overall?

“At a theoretical level, timing probably doesn’t have much impact,” suggests Prof Liston. “There would be immunological differences based on the timing of the dose, but the vaccine works so well that it is highly unlikely to alter the outcome at the level of protection from clinical disease, which is what actually matters.

How the Pfizer/BioNTech vaccine works
How the Pfizer/BioNTech vaccine works

“The immune system has a memory that can last decades, so a shift from four weeks to 12 weeks is highly unlikely to have any detrimental effect in the ability of the immune system to learn.

“At a practical level, the preference is always to use something proven to work and not to alter it on the run. Four-week boosters work, so under normal circumstances we would just keep four weeks as the booster. So even though there is no real cause for concern in shifting from four weeks to 12 weeks, it is better not to change something that works unless there is a very good reason to do so.”

For the government, the rapid spread of the new variant of the Covid-19 virus provided that reason.

Some have argued against the decision – and even Pfizer/BioNTech, which produced the first vaccine approved in the UK, queried it, pointing out that their clinical trial data related to jabs spaced 21 days apart.

Pfizer said in a statement: “Data from the Phase 3 study demonstrated that, although partial protection from the vaccine appears to begin as early as 12 days after the first dose, two doses of the vaccine are required to provide the maximum protection against the disease, a vaccine efficacy of 95 per cent.”

So was it the right call?.

“There is some controversy around this, but my thoughts are in line with the views of the British Society for Immunology,” says Prof Liston, pointing to the society’s statement.

“Essentially, the ideal situation is to shut down transmission by effective social distancing. We would then roll out the vaccine using the already-tested four-week booster schedule, with a first focus on care-home residents and workers, health workers and high exposure professions – teachers, shop assistants etc.

“We would have high density asymptomatic testing, and in the next phase we would ‘ring-vaccinate’ areas that showed local spikes in infections, to prevent the outbreak spreading.

“Finally we would broadly vaccinate the entire population, which could be done simultaneously with easing off the social distancing measures.

Illustrative vaccine vials from AstraZeneca / Oxford University. Image: AstraZeneca
Illustrative vaccine vials from AstraZeneca / Oxford University. Image: AstraZeneca

“However, the decision on vaccination cannot be made in a vacuum. The ideal situation above would be viable in countries such as Belgium or Australia, which have come down from the second wave.

“It does not describe our current situation in the UK, where we are still near the peak of the third wave. In effect, by failing to prevent a third wave through social distancing measures, the UK has lost the ability to follow through on the ideal response approach.

“Given this context, the question becomes one of risk assessment. We know that the vaccine will save many lives, so are we willing to make an educated modification to the schedule to front-end load the protection?

“Here I would say yes, it does make sense to delay the second dose to 12 weeks, so that we can extend the reach of the vaccine during an active outbreak. This is also the view of the British Society for Immunology.”

But he argues: “This is not optimal, and is occurring because of a situation created by previous policy failures, but given everything we know about the immune response to vaccines it does seem to be a reasonable and educated modification.

“This does come with several provisos, however: one, the outcome should be monitored in real-time, by providing data to experts, and the NHS should be prepared to rapidly shift their decision if the evidence goes against the change; and two, there could be a case that a subset of individuals – eg those in the highest risk category – could be prioritised to a second dose at the original schedule of four weeks.

“In other words, we can make a split decision for different age groups, depending on how fast vaccine production can be ramped up.”

Meanwhile, genomic surveillance from the Cambridge-led COG-UK consortium continues to monitor the emergence and spread of variants of the virus amid concern about the impact of mutations, which naturally occur as a virus spreads.

The variant responsible for the UK’s third wave of Covid-19 is understood to be 50 to 70 per cent more transmissible, while other notable variants being studied have emerged in South Africa and Brazil.

There has been concern – although it is known – that changes to the spike protein that approved vaccines act against could impact on the effectiveness of our vaccines.

But Prof Liston suggested the balance of probability is on our side.

A vaccination is adminstered. Picture: PA
A vaccination is adminstered. Picture: PA

“Most likely the vaccines will remain largely effective, as there is a broad response generated,” he said. “Even if the vaccine is not entirely effective, it should still reduce the severity and death rate.”

Health secretary Matt Hancock has said we can expect annual Covid-19 vaccinations – at least for a time.

“I think it’s highly likely that there will be a dual-vaccination programme for the foreseeable, this is the medium-term, of flu and Covid,” he told Sky News.

Prof Liston explains: “In an ideal situation, global vaccination would eradicate SARS-CoV-2. Previous coronavirus outbreaks – SARS, MERS – were eradicated, and initially that was an option available for SARS-CoV-2.

“Unfortunately, the depths of the outbreaks around the world make complete elimination a much more difficult task, and it is possible that SARS-CoV-2 becomes an endemic virus. That doesn’t mean that everyone needs to be vaccinated every year, but it does mean we will need to try to keep up population vaccination rates for at least several years, and it is possible that this gets permanently incorporated into the routine childhood vaccine schedule.”

The flu vaccine, however, has to be altered annually to keep up with its different strains.

Prof Liston suggests that was “unlikely” with Covid-19.

“Flu is quite a unique virus, and really we shouldn’t consider it to be one virus. Instead there are many, many different flu viruses.

“Flu has the ability to recombine different flu viruses into unique combinations, and major outbreaks occur when duck flu and human flu recombines, often in pigs. So flu vaccine science is a matter of trying to guess which new combination is coming and getting ahead of the curve. SARS-CoV-2 does not have this ability to recombine and,

while mutations are possible, they will cause an evolution at a much slower rate. Minor adaption of the vaccine could occur when needed, but we won’t have the issue that we do with flu.

“More importantly, given the failures to control SARS2, are we ready for SARS3 when that occurs? Because it is a matter of when, not if.”

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