The headlines, when they came, were chilling. “Two Alaska health workers got emergency treatment after receiving Pfizer’s vaccine”, read the front page of the New York Times in December 2020. “Possible link between J&J Covid vaccine and rare blood clots, EU regulator finds”, reported the Guardian a few months later. By June 2021, the Daily Mail had splashed the story of Tanya Smith, a healthy mother who died of blood clots days after her jab. Quoting her partner, the paper described Smith as “just amazing, selfless. She was a childminder – a really good childminder for 19 years”. When she died, leaving behind three young children, Smith was just 43 years old.

Stories like this are always depressing to read, especially given how readily they’re exploited by vaccine sceptics. As a popular comment on the Mail’s story wailed, Smith’s death was just another example of officials “downplaying” the risks of Covid-19 shots, a sentiment echoed across social media. Naturally, it’s easy to dismiss these people as paranoid conspiracy theorists. But given one-third of people in the US are still reluctant to get their shot, it’s probably worth asking whether they have a point.

Of course, that doesn’t mean entertaining the notion that governments are deliberately obscuring the true cost of vaccines, let alone that every dose contains tiny 5G microchips. All the same, it’s undoubtedly true that every Covid-19 jab comes with some inherent risks. Despite these challenges, you sometimes get the sense that many lay enthusiasts would struggle to explain how vaccines actually work, while even pharmaceutical experts seem reluctant to clarify why a few unlucky people suffer anaphylactic reactions or blood clots after getting jabbed. Understanding the truth, however, is worth the effort – if only because it shows that the threat of Covid-19 is still far worse than any vaccine.

A shot in the dark?

It’s tempting for a layperson without knowledge of immunology to imagine that vaccines are simple – that they’re just the unadulterated active ingredient of a drug. In truth, all pharmaceuticals are also laced with excipients. They may not have a direct role in offering protection against illnesses like Covid-19, but as Viktorija Erdeljic Turk explains, excipients are still vital to the general package. “Excipients are basically everything other than the active pharmaceutical ingredient,” says Turk, a consultant clinical pharmacologist and toxicologist at University Hospital Centre Zagreb. In practice, Turk continues, this encompasses everything from chemicals that contribute to a drug’s biopharmaceutical profile to ones that change its appearance.

What about the excipients in Covid-19 vaccines? That depends on the drug. The AstraZeneca jab contains a common excipient known as polysorbate 80, which increases its stability. The Moderna and Pfizer-BioNTech mRNA vaccines, for their part, contain another stabilising excipient called polyethylene glycol. As Lene Heise Garvey explains, that’s important because of how they work. Like viral vector vaccines, they enable cells to make a protein that triggers an immune response specific to, in this case, Covid-19. A vital component necessary for making that happen are fatty molecules called lipid nanoparticles, which mRNA vaccines use in place of modified viral vectors like AstraZeneca’s adenovirus. These LNPs disguise the mRNA so that it isn’t recognised by the body as foreign matter and destroyed.

Polyethylene glycol helps combine the mRNA and the lipid nanoparticles. As Garvey, an associate professor at the University of Copenhagen, puts it: “The lipid nanoparticles have to be intact for this messenger RNA to go into the cells, and the polyethylene glycol holds them together.” All well and good. But that still leaves one question unanswered: what do these different excipients have to do with serious reactions to vaccines? It turns out the answer is potentially quite a lot. Though it’s common across the food and pharmaceutical industries, for instance, polysorbate 80 has occasionally been linked to serious reactions in users, including anaphylaxis. At the same time, polyethylene glycol might come with similar risks. We already know, after all, that penicillin and laxatives can cause anaphylaxis, and that they contain polyethylene glycol.

By December 2020, no reactions to polyethylene glycol had been reported in vaccines – but then again, the Moderna and Pfizer Covid-19 vaccines are among the first to contain the excipient. One potential risk is that, due to structural similarities, polyethylene glycol and polysorbate 80 can spark cross-reactivity. This, in effect, means that though someone is allergic to polysorbate 80, exposure to polyethylene glycol makes them react in a similar way. What is certain, at any rate, is the danger of allergic reactions like anaphylaxis. At best, it can encourage rashes and wheezing. At worst, it can trigger cardiac arrest and death. And that’s before you consider the blood clots that killed Tanya Smith, which could have been the result of a misguided assault by her own autoimmune system.

“The lipid nanoparticles have to be intact for this messenger RNA to go into the cells, and the polyethylene glycol holds them together.”

Lene Heise Garvey, University of Copenhagen

A right jab

Given these potential dangers, how should a responsible public approach Covid-19 vaccines? Both Turk and Garvey suggest looking at the numbers. A fair point, even if you only consider a single country. In the US, for example, just one of the 18,801 participants in a late-stage trial for the Pfizer vaccine had an anaphylactic reaction. These numbers reflect a broader truth: vaccines can harm you, but only if you’re extremely unlucky. As a 2015 study by the Centers for Disease Control and Prevention (CDC) found, 33 confirmed cases of vaccine-triggered anaphylaxis were found among 25 million doses. That translates to a rate of just 1.3 cases for every million doses. No wonder Turk emphasises that the risk of anaphylaxis is both “extremely low” and “offset by the benefits of the vaccines”.

That last point is important. If the threat of Covid-19 was smaller than the risk of the vaccine, you could plausibly argue that getting the jab wasn’t worth it. As it is, this isn’t the case.

“Having established allergy investigation protocols would certainly increase vaccine acceptance, especially in people that experienced an allergic reaction to a Covid-19 vaccine.”

Viktorija Erdeljic Turk, University Hospital Centre Zagreb

If you contract the virus as an 85-year-old, you have a 15% chance of dying. Even for people in their 20s, the risk of death is around four in 1,000. Given how much more likely that is than getting anaphylaxis from the vaccine itself, Garvey suggests that the “risk-benefit” calculation of getting jabbed should be straightforward. Nor, adds Garvey, is this balancing act unique to Pfizer, AstraZeneca and the other Covid-19 vaccines. All drugs, right down to everyday medications like paracetamol, have rare and potentially lethal side effects too.

Clearly, none of this means that clinicians are abandoning people to their fate, crossing their fingers that their next patient isn’t that one-in-a-million anaphylaxis sufferer. On the contrary, numerous safeguards are embedded deep into the vaccination process. For one thing, people are typically asked to wait for around 15 minutes after getting a jab. Given most anaphylaxis reactions happen almost immediately after an injection, this tactic helps doctors spot sick patients.

In a similar vein, workers in vaccination centres are normally trained in spotting the signs of anaphylaxis. More broadly, Turk and her colleagues are working to develop protocols that can confirm if someone is prone to anaphylaxis. It goes without saying, explains Turk, that “having established allergy investigation protocols would certainly increase vaccine acceptance, especially in people that experienced an allergic reaction to a Covid-19 vaccine.”

Inherent risks

Beyond tests to reassure hesitant punters, there are clearly many ways to boost confidence in the vaccine programme. One is to fully explain the statistics around risks and benefits. Given one 2013 survey in the US found that four in five people can’t understand statistical problems, better education might help – if only to banish the false idea that numbers like ‘four in 1,000’ mean that one in 250 youngsters who catch Covid-19 are definitely going to die. From there, Turk suggests that robust campaigns against misinformation are vital, especially if they’re spearheaded by doctors themselves. “Healthcare professionals should do their utmost to convince their patients of the benefits of vaccination,” she says, “and lead by example.” And, as Turk adds, though dedicated anti-vaxxers can likely never be convinced to get jabbed, research shows that a “significant proportion” of the undecided can be influenced in time.

Even so, this optimism will need to be tempered by an acceptance that all drugs carry an inherent risk, and that a few people will continue to pay a terrible price. Excipients are just too important for medications the world over, and scientists are doing everything they realistically can to keep patients safe. To put it another way, there will sadly be more cases like that of Tanya Smith in the months and years ahead. But look past these personal disasters, and it seems clear that vaccines will continue to lead the fight against Covid-19 – and prevent many more needless deaths.

Vaccine hesitancy in numbers

The majority of the world understands that vaccination is a necessary measure to not only protect individuals, but also curb the spread of the SARS-CoV-2 virus – yet statistics show much higher hesitancy in some countries than others. The US is a particular hotspot for anti-vaccine sentiment at the moment, with the situation termed by politicians and physicians as “a pandemic of the unvaccinated” – a view supported by CDC study findings that those who forgo the jab are 29 times more likely to be hospitalised with Covid-19. Courtesy of polling company Morning Consult, here are 15 countries ranked by their level of vaccine hesitancy:

Source: Morning Consult (data is correct as of 18 October 2021)