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The cases are already beginning to emerge.
When 85-year-old Colin Horseman was admitted to Doncaster Royal Infirmary in late December, it was for a suspected kidney infection. But not long afterwards he caught Covid-19 – at the time, roughly one in four people in hospital with the virus had acquired it there. He developed severe symptoms and was eventually put on a ventilator. A few days later, he died.
At first glance, Horseman's situation may seem fairly typical, though no less tragic for it. After all, at least 84,767 people have now succumbed to the disease in the UK alone at the time of writing. But, as his son recently explained in a local newspaper, less than three weeks earlier he had been among the first people in the world to receive the initial dose of a Covid-19 vaccine – the Pfizer-BioNTech version. He was due to receive the second dose two days prior to his death.
In fact, most vaccines require booster doses to work.
Take the MMR – measles, mumps and rubella – vaccine, which is given to babies around the world to prevent these deadly childhood infections. Around 40% of people who have received just one dose are not protected from all three viruses, compared to 4% of those who have had their second. People in the former group are four times more likely to catch measles than those in the latter – and there have been outbreaks in places where a high proportion of people have not completed the full MMR vaccination schedule.
"The reason that people are so keen on boosters and consider them so vital is that they kind of send you into this whole other kind of fine-tuning mode of your immune response," says Danny Altmann, professor of immunology at Imperial College London.
How booster vaccines work
When the immune system first encounters a vaccine, it activates two important types of white blood cell. First up are the plasma B cells, which primarily focus on making antibodies. Unfortunately, this cell type is short-lived, so although your body might be swimming in antibodies within just a few weeks, without the second shot this is often followed by a rapid decline.
Then there are the T cells, each of which is specifically tailored to identify a particular pathogen and kill it. Some of these, memory T cells, are able to linger in the body for decades until they stumble upon their target – meaning immunity from vaccines or infections can sometimes last a lifetime. But crucially, you usually won't have many of this cell type until the second meeting.
The booster dose is a way of re-exposing the body to the antigens – the molecules on pathogens that trigger the immune system – to initiate part two of the response. "You've kicked in all this fancy stuff," says Altmann. "So, once you've had your boost you'll have a higher frequency of memory T cells and ditto to some extent for the size of the pool of memory B cells you'll have. They'll also be making higher quality antibodies."
On second exposure to the same vaccine or pathogen, the B cells that remain from before are able to rapidly divide and create a menacing throng of descendants, leading to a second spike in the amount of antibodies circulating.
Manufacturing enough of each of the vaccines will take time, so some countries – such as the UK – have decided to delay the second dose (Credit: Alamy)
The second dose also initiates the process of "B cell maturation", which involves selecting the immature ones with the best receptors for binding to a particular pathogen. This happens while they're still in the bone marrow – where white blood cells are made – and afterwards they travel to the spleen to finish developing. This means B cells are not only more numerous afterwards, but the antibodies they produce are better targeted.
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Memory T cells, meanwhile, also proliferate rapidly. They're already thought to have played a critical role during the current pandemic, protecting some people from developing severe Covid-19. Though the virus may have only been circulating globally since around December 2019, there's some evidence they may have "seen" other coronaviruses before, such as those that cause the common cold – allowing them to recognise Covid-19.
So how effective is a single dose of each of the Covid-19 vaccines?
At a time when the answer is more urgent than ever – especially as the British government has decided to delay the second dose of all currently approved Covid-19 vaccines from 3-4 weeks to 12, and Russia is trialling a single-dose regimen of its Sputnik V vaccine named "Sputnik-Light" – it's also surprisingly complicated. Here's what we know so far.
According to Pfizer data published in December 2020, the Pfizer-BioNTech vaccine is roughly 52% effective after the first dose. Out of 36,523 participants in the phase three trial – the final stage of testing where people either received two full doses, 21 days apart, or a placebo – who had no evidence of existing infection, 82 people in the placebo group and 39 in the vaccine group developed Covid-19 symptoms.
Preclinical trials would have shown that they didn't think there was enough immunity after one shot. So they've gone for both – Deborah Dunn-Walters
However, this early protection comes with some important caveats. First, the protection doesn't kick in until at least day 12 – until then, there was no difference between the two groups. Secondly, one dose is still significantly less protective than two. The latter is 95% effective at preventing the disease after a week.
But there is also another figure that has been circulating on the internet, and anecdotally, being fed to patients by certain doctors – the suggestion that the first dose is around 90% effective. And this is where it gets a little more complicated.
The second estimate comes from the UK's Vaccine Committee, the JCVI, who decided to calculate the efficacy of the vaccine differently. Instead of using all the data on the number of infections, including from days when the first dose hadn't yet started to work, they only looked at days 15-21. Using this method, the efficacy of the vaccine jumps up to 89%, because it's not being diluted by the relatively high number of infections before the vaccine begins to have an effect. Taking things even further and only looking at the first seven days after the second dose (days 21-28) – because the second dose might not have kicked in yet by then – it's 92%.
However, these calculations are controversial.
A vaccine developed to fight Ebola is the only one that uses the same technology as the Russian and Oxford-AstraZeneca Covid-19 jabs (Credit: Getty Images)
"People are very keen on at the moment on that graph in the Pfizer paper in the New England Journal of Medicine where they show that there must be some kind of de facto benefit as early as something like day 14," says Altmann. "It's the one where the curve for the placebo group and the vaccine group completely diverge, and cases start taking off in the placebo group. But obviously that's not measuring an immune response directly – it's using quite a crude measure of how many people have been infected." Altmann explains that he wouldn't advise anyone to consider themself safe 14 days after their first dose of the vaccine. "The graph is just a way of saying 'something is happening'," he says.
In a more recent development, an Israeli academic who coordinated the country’s Covid-19 response – Professor Nachman Ash – has claimed that a single dose of the vaccine is not as effective as Pfizer originally estimated. However, the comments have been widely criticised.
There are a number of reasons that it is inappropriate to compare the research, which was conducted by the health organisation Clalit, with the Pfizer study. For one, the Israeli study found that a single dose of the vaccine reduced the number of people testing positive for the virus, i.e. being infected, by 33%, while the Pfizer paper suggested that it would prevent 52% from developing symptoms – they looked at two different things.
In addition, the data from Clalit has not been made available, or peer-reviewed. It also involved examining the impact of the vaccine just two weeks after people had received it – considered too early to see an immune response – rather than three, as in the Pfizer study. Finally, the research was not a clinical trial, but rather an observational study, which means the results should be viewed with caution.
For the Oxford-AstraZeneca vaccine, things are a bit different. In a paper published in January, the authors explain that the vaccine offers protection of 64.1% after at least one standard dose. This compares to 70.4% if you've had two full doses, or – oddly – 90% in people who have had one half dose followed by one full dose.
A month later, AstraZeneca revealed the results of a first analysis of their phase III trial data in a press release. Starting from 22 days after the first dose, the vaccine provided 70% protection against mild or moderate illness and 100% against severe disease, hospitalisation and death.
Because the phase three trial included two gaps between the first and the second dose – including one of six weeks and a longer one of 12 weeks – it's possible to say with more certainty that the first dose can continue to provide some protection for at least a few months before the booster shot.
According to a document the company submitted to the FDA, the Moderna vaccine can provide 80.2% protection after one dose, compared to 95.6% after the second (in people aged 18 to 65 – it's 86.4% in those over 65). As with the Pfizer vaccine, all participants in the phase three trial received two doses of the vaccine or a placebo within a single set time period – in this case, 28 days – so it's not yet known whether the immunity from a single vaccine would continue, or drop off after this stage.
The CoronaVac vaccine was developed by Sinovac, a biopharmaceutical company based in Beijing, China. This version is unusual as it has been trialled independently in several countries – all of which have produced different results.
According to researchers in Turkey, the vaccine is 91.25% protective, while scientists in Indonesia have said that it’s 65.3% effective, and the Butantan Institute in São Paulo, Brazil recently announced that the vaccine prevents 50.4% of people from developing symptoms. At the moment, no one has released data on the efficacy of a single dose – these figures only apply to two doses, spaced 14 days apart.
The results have been viewed with some scepticism, because they were published via press releases, instead of – as would normally be the case – in a peer-reviewed journal. Without access to more information about the trial methods and the data that was collected, it’s harder for scientists to make their own assessments of the results' validity.
In all, there are five Chinese vaccines at various stages of development.
Another is "BBIBP-CorV", by the state-owned company Sinopharm, based in Shanghai. Officials in the country recently announced that this version is 79% effective after two doses – though by then, it had already been distributed to nearly a million people. This estimate has not been verified by the international community, because the underlying data and methods for its trial have not been made publicly available. It's not yet clear how protective it might be after a single dose.
Outside China, the vaccine is currently being tested all over the world, and has been approved in Bahrain, Egypt, Jordan, the Seychelles, and the United Arab Emirates. The UAE recently became the first to rate its efficacy, claiming via a press release that it is 86% effective.
Most of the Covid-19 vaccines that have been developed target the "spike protein" on the virus' surface (Credit: Getty Images)
The Sputnik V vaccine is named after the world's first artificial satellite, the iconic Soviet-era "Sputnik 1", which was launched into low Earth orbit in October 1957 – it burned up three months later when its batteries died. Its namesake was developed by the Gamaleya Research Institute of Epidemiology and Microbiology in Moscow, Russia.
As with the others, this vaccine is administered as two doses, and is apparently 91.4% effective after both – there is currently no publicly available information on the efficacy of just one dose.
Again, these results haven’t been published in a peer-reviewed journal and therefore may not be reliable. Despite a rapid rise in the number of Covid-19 cases in the country, the vaccine’s safety and efficacy has been viewed with suspicion by many Russians, according to a report in the Washington Post. In the first week it was rolled out in December, clinic waiting rooms were reportedly half-empty.
More recently, the Russian government announced that it was developing a new version, "Sputnik-Light", as a temporary solution to shortages of the original. The vaccine would be delivered as a single dose, though it's not yet clear how protective it would be.
Can you change your behaviour after receiving a single dose?
"I would behave exactly as if I hadn't had the vaccine yet," says Altmann. "I wouldn't drop my guard at all or do anything differently."
Deborah Dunn-Walters, professor of immunology at the University of Surrey, is just as unequivocal about how people should behave. "There's a couple of reasons for that," she says. "One is, you're not going to be fully protected. And another is there is no evidence as yet that having had the vaccine will stop you getting the virus and passing it on."
Dunn-Walters explains that the efficacy of the vaccines were largely assessed by looking at whether they prevented people from developing symptoms – not if they stopped them being infected with the virus. "And we do know that it's possible to have asymptomatic infection," she says. There is not yet any evidence that one dose – or even two – of the existing vaccines will stop people from giving the virus to others.
Can you skip the second vaccine dose?
"Preclinical trials would have shown that they didn't think there was enough immunity after one shot. So they've gone for both," says Dunn-Walters. Similarly, during phase three trials, there were more antibodies and T cells in the blood after two doses than there were after one.
Immunity can take weeks to emerge, so Covid-19 vaccines can't protect you immediately (Credit: Getty Images)
As the chief executive of Pfizer, Albert Bourla, explained in December that it would be a "big mistake" to skip the second dose, because it almost doubles the amount of protection you get.
Pfizer and BioNTech themselves have already urged caution on the grounds that their data ends at day 21, and "there is no data to demonstrate that protection after the first dose is sustained after 21 days". It's possible that the protection people seem to have will suddenly drop off after that point – in fact, this wouldn't be surprising based on the way the immune system usually works.
Reliably estimating how long the protection from a single dose might last is further complicated by the fact that all the currently approved Covid-19 vaccines are using brand-new technology.
The Oxford-AstraZeneca and Sputnik-V vaccines both involve modified versions of adenoviruses – a group that can break into many different cell types and cause a range of illnesses, such as respiratory infections. While the Oxford version uses an adenovirus from chimpanzees, the Russian one includes a mixture of two human types.
The virus was altered for the vaccines so that it's safe and can't make more copies of itself inside cells. It is able to teach the body to recognise the coronavirus by encoding the instructions to make a feature found on its surface, the spike protein.
Though adenoviruses have been used in cancer vaccines and gene therapy for years, they had only ever been used once before to prevent a viral infection – an Ebola vaccine using this method was approved for use in European Union countries in July 2020.
It's not yet clear how long the partial protection provided by a single dose of any of the Covid-19 vaccines will last (Credit: Getty Images)
The Moderna and Pfizer-BioNTech versions, on the other hand, are arguably even more pioneering. Both contain countless miniscule fragments of mRNA, which – as with the adenovirus-based vaccine – encode the spike protein from the surface of Covid-19. They are the only mRNA vaccines to have ever been approved for use in humans.
Without other mRNA vaccines to compare them to, the world is in uncharted territory. As Ronald Corley, professor of microbiology at Boston University, recently explained in an interview with the university news magazine, there are many unknowns, such as whether they will work just as well in people from different ethnicities, and how long immunity will last.
The Sinovac and Sinopharm versions contain inactivated coronavirus particles instead. This method is less unusual – the concept of using dead pathogens in vaccines has been around since the late 19th century. However, it’s no less clear how long the immunity will last, since no vaccines made from a member of this virus family had ever been approved before the pandemic.
Immunity takes time to develop
Finally, Dunn-Walters is keen to point out that immunity takes time to develop – so regardless of whether a single dose of any of the Covid-19 vaccines can provide protection eventually, for the first couple of weeks you will have no more than you started with.
"There's a part of the immune system which we call innate immunity, which responds immediately," says Dunn-Walters. This encompasses physical barriers to infection, like your skin, as well as certain types of white blood cell and chemical signals. But she explains that this generally can't prevent disease on its own – and isn't affected by vaccines. "So you need adaptive immunity as well. But the issue with adaptive immunity is that, as its name says, it's adaptive – it adapts to individual challenges by pathogens."
For vaccines to have any effect, they must encourage the body to make more immune cells – some of which in turn produce antibodies. "And this takes time," says Dunn-Walters.
So while the global roll-out of the new vaccines may be exciting, it looks like most of us will have to wait a while longer before normal life can resume.
This story was updated on 18/1/2021. An earlier version incorrectly stated that an Ebola vaccine using adenoviruses had been approved for use in the US. Separately, it said that the CoronaVac vaccine was tested by the UAE. The Ebola vaccine has been approved for use in the European Union and the UAE tested a different vaccine, made by the company Sinovac. The article was also updated on 21/04/21 with new information about the efficacy of one dose of the Oxford-AstraZeneca vaccine.
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