Still a lot of work needed on vaccines, experts warn
As the world seeks to develop a coronavirus defence, scientists say public must not get carried away by unrealistic expectations
In 1976, when a mysterious new flu began spreading in the north-eastern United States, a few months before the presidential election, Gerald Ford, the then US president, raced ahead with a high-profile campaign to vaccinate the nation. The flu strain turned out to be rather mild and, worse still, the vaccine caused several hundred people to develop paralysing Guillain-Barré syndrome.
That debacle is central to the story of why the American public has such an uneasy relationship with vaccines. It’s also a precedent that worries the scientific community as they wrestle with how to deal with a hesitancy over vaccines and overblown expectations for a potential coronavirus vaccine.
Even the smallest, unwarranted cause for doubt could deal a severe blow to the cause of global health. But so, too, could a failure to match unrealistic expectations held by a public that is desperate for good news.
The process for ensuring vaccines
are safe is well established and they are held to a much higher standard of safety than normal medicines, explains Dr Mike Turner, head of major science investments at the Wellcome Trust, a biomedical charity which funds global vaccine research. “Inevitably, the safety bar is higher for vaccines than for drugs, because drugs you give to people who are already ill, vaccines you give to healthy people”.
Many of the usual trial phases for vaccines are being run in parallel for Covid-19 candidates, but Dr Turner is adamant that what is taking place is not cutting corners. The most advanced vaccine projects are moving into large scale Phase 3 trials in which any less-common side effects or safety issues should become apparent.
Side effects are common and can be wide ranging, but not a significant barrier to receiving a jab. Some, however, might be so rare as to not emerge until there is population-scale deployment of a vaccine.
Maurice Hilleman, an American microbiologist who developed over 40 vaccines, is said to have claimed he only relaxed once the three millionth dose of a new vaccine had been given.
That wasn’t without reason; these rare adverse effects can be serious. The 1976 case is one example, as is Pandemrix, a vaccine for swine flu given to around six million people in the UK in 2009 and 2010. It was found to cause narcolepsy, a debilitating sleep disorder, in around one in every 55,000 vaccinated individuals in the UK, or just over 100 people.
The classic example, says Prof Naor Bar-Zeev, an infectious diseases physician and statistical epidemiologist at Johns Hopkins University’s International Vaccine Access Center, is that of RotaShield, a vaccine against diarrhoea-causing rotaviruses released on the American market in the late Nineties. The vaccine was linked to a very small number of cases of intussusception, a life-threatening intestinal disorder, and was rapidly withdrawn from use.
A replacement wasn’t available for close to a decade and in that time, says Prof Bar-Zeev, “many hundreds of thousands of children died from diarrhoeal diseases that would have been averted had that so-called ‘bad’ vaccine been available”.
The key point, he says, is that, “despite their phenomenal contribution to health, all vaccines carry some risk and it’s a societal, ethical and a political decision about what the right balances of risks are.”
Crucially, those decisions have to be communicated clearly: “The world is already mistrusting of vaccines and we cannot roll out a vaccine to the whole world if it causes harm; even if that harm is very limited and even if as is expected the benefit far outweighs the risk, it still has to be very clear what those risks are so people understand the balance of benefit vs risk.”
When drugs pass Phase 3 trials and enter into widespread use they are not simply forgotten about by regulators and scientists. Instead, a fourth phase, known as pharmacovigilance, is in place to monitor for and respond to any suspected adverse outcomes.
In the case of Covid-19, that will be the key to guaranteeing public trust.
Fake news is already out there, says Prof Beate Kampmann, director of the Vaccine Centre at the London School of Hygiene and Tropical Medicine.
“There is already stuff on social media saying this vaccine was tested on children in Africa and they all died, it’s presented in a very emotional way, and once that’s out there it’s very difficult to fight that false information.”
Once a vaccine is deployed, the risk of scares will increase risk perception and not just from total fabrications. “Let’s say there’s a report of early pregnancy losses,” says Prof Bar-Zeev. “It’s totally coincidental to the vaccine, but it gets reported as ‘this thing kills babies’ and then people stop taking it”.
However, the unprecedented scale of any vaccination programme will create both significant challenges and ethical questions.
Prof Bar-Zeev says that any coronavirus vaccine is likely to be given to people who are not usually vaccinated, such as healthy adults, who tend not to be monitored.
Likewise, says Prof Kampmann, while the UK and other developed nations have established pharmacovigilance systems in place, many poorer countries do not. That could lead to difficult questions, she says. “You might decide we won’t use that vaccine in Africa until we have got significantly more safety information, but you might have protected thousands of people from getting it.”
Whatever decision is made, none of these questions will be handled “willy-nilly” Prof Kapmann says, but it is essential the public be made aware of how they are debated if confidence in vaccines is to be maintained.
Getting the message across that there is a vast network of regulation and monitoring behind the vaccine might also inject a dose of realism into expectations. There is a concern among scientists that the media and political hype is building up huge expectations that will both undermine the fight against Covid-19 and damage confidence in vaccines as a whole.
Not only is this going to be a slow
‘Despite their phenomenal contribution to health, all vaccines carry risk and it’s a societal, ethical and a political decision about what the right balances are’
process, but it’s one with plenty of potential for setbacks, which could, ultimately, prove inconclusive.
One of the most basic issues is that, while early trials have delivered positive results, they are still very far from being guaranteed to work.
Once those vaccines are tested on tens of thousands of people in Phase 3, there’s plenty of potential for failure. One of the greatest setbacks could be caused by antibody-dependent enhancement (ADE), also known as disease or immune enhancement. It’s a rare phenomenon in which the presence of antibodies in an individual can trigger a worse infection.
Efforts to develop vaccines for Sars and Mers found evidence of ADE in animals. In other cases, it has been a major setback. Prof Bar-Zeev cites the case of a vaccine developed in the late Sixties for RSV, a common childhood illness, in which ADE is suspected as the cause of its failure. “The vaccine was withdrawn from the market 51 years ago and we still don’t have a good RSV vaccine. The safety of a Covid-19 vaccine is essential.”
Even if Phase 3 trials are passed with flying colours, manufacturing to scale could take a long time and there is always the possibility of a RotaShieldtype event which would call for a serious ethical debate.
Just as concerning as the safety issues is the still unanswered question of efficacy. It may be that, while candidate vaccines turn out to be quite safe, they aren’t anywhere near effective enough to be worth using.
Vaccines can have the very useful effect of reducing the severity of infection, but the holy grail for a coronavirus vaccine would be to prevent transmission as well. Given the still uncertain nature of immunity to Covid-19 and how long lasting it is,
‘The world is already mistrusting of vaccines and we cannot roll out a vaccine to the world if it causes harm; even if that harm is limited and outweighs the risk’
that could be an unachievable goal.
“If the immunity is short-lived then it’s a little bit futile because to mount a massive campaign every few months to vaccinate the world is not going to be sustainable,” says Prof Kampmann.
Such a vaccine would not be useless, as it would protect the individual, but it’s a long way from the notion some seem to have that, as Prof Kampman puts it, “all we need is this one vaccine and the show is over”.
More than just generating disappointment, scientists worry that over-hyped expectations for a vaccine risk creating serious problems. Public faith, too, is at stake. The public need to be made aware of the stringency with which vaccines are vetted, says Prof Kampmann. If the public isn’t, and it turns out that a Covid-19 vaccine can’t be made to work, then “the credibility of immunisation systems as a whole could crash”.