How safe are vaccines?

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During this challenging time, discovering and producing a safe and effective coronavirus vaccine in a short period of time is a formidable challenge, but not the only one. Despite the evident benefits of vaccines (10 million deaths were saved by vaccines just in 2010-2015), the influence of anti-vaccination movements is increasing. However, history shows us that this is not a new phenomenon.

In eighteenth-century Britain there were no vaccines and smallpox was the most lethal infection. Protection could be acquired only through variolation, which consisted of inoculation with the pathogenic virus. The choice was difficult: variolation carried a 2-3% risk of death, but if you caught smallpox the risk was 30%.

Discovery of a smallpox vaccine was initially met with scepticism if not hostility. Jenner used a live virus derived from a similar infection in cows (cowpox). In this caricature, by James Gillray, those undergoing vaccination are portrayed as having cows emerging from their bodies.
Image from wikimedia commons

Jenner’s pioneering development of the smallpox vaccine in 1796 was a game changer. Jenner used vaccinia, a live attenuated virus, which would cause a mild infection in humans. All subsequent vaccines have been based either on live attenuated viruses or inactivated viruses or even just selected components from viruses and bacteria.

Both vaccines and medications can cause side-effects.  Medications used for the treatment of life-threatening conditions may be acceptable even if there was a risk of severe side-effects. Vaccines, though, are administered to healthy subjects: thus, we need to be sure they do not cause any severe side-effects.

The safety of a new vaccine is demonstrated in phase 2 and phase 3 clinical studies, that typically, enrol between 2,719 and 86,801 volunteers. The number of individuals in these studies, especially at the lower end, does not guarantee that side-effects occurring at an extremely low frequency will be detected.

Thus, it is equally important to monitor the occurrence of side-effects after a new vaccine has been licensed for use: this is known as post-marketing surveillance. As vaccines are given to many millions of recipients, quite a few individuals may report apparent side effects. Detailed epidemiological and statistical analyses are required to differentiate causality from coincidence.

In the mid 1970s concerns about possible severe side-effects with the pertussis were raised, and in the late 1990s questions were raised about the measles vaccine in the combination MMR but the safety of these vaccines has been subsequently demonstrated.

Conversely, when post-marketing surveillance of the first Rotavirus vaccine identified some cases of a severe side-effect (a bowel complication called intussusception), a subsequent investigation by the US CDC showed a genuinely increased risk at a frequency of one or two cases per 10,000 vaccines. Modified Rotavirus vaccines were subsequently developed with a larger number of individuals in the phase 3 trials.           The World Health Organisation position paper on the new Rotavirus vaccines in 2013 concluded that with the new vaccines the risk of intussusception is much lower (1 or 2 cases every 100,000 vaccines) and lower than the risk of severe diarrhoea and death from rotavirus infection.

In the Spring of 2009, a new influenza strain emerged that caused a small-scale pandemic. As the existing influenza vaccine offered little cross-protection, new vaccines had to be produced in a short time. One of these new vaccines (Pandemrix) was associated with narcolepsy, a severe neurological complication in children, which in England occurred at a rate of about one case for every 50,000 vaccinations. However, it has also been suggested that influenza infection might also cause narcolepsy and there is still uncertainty in relation to what was the role of Pandemrix.

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Vaccine uptake in the UK varies. With childhood vaccines like the measles, mumps and rubella (MMR) uptake is just below the 95% target. However, with the influenza vaccination in adults aged 65 and over the uptake is just over 70%. This lower uptake may reflect fatigue, as the seasonal influenza vaccine needs to be repeated every year, or a perception of influenza as a less severe illness.

The belief that vaccines cause significant side-effects is associated with vaccine refusal. Equally, information seeking behaviour has also been associated with vaccine refusal, possibly because of negative views about vaccination in some websites and social media.

Professor Julie Leask has argued that there is not a simple division between vaccine acceptors and non-acceptors: there are ‘cautious acceptors’ as well as ‘hesitant acceptors’ and ‘selective vaccinators’ who may accept some vaccines but not others. Then, there is a group refusing all vaccines. The vaccine promotion campaign needs to be carefully thought through, with emphasis on the collective and not just the individual benefits. The Prime Minister, Boris Johnson, recently said that “all anti-vaxxers are nuts” , but it would seem from Prof Leask’s analysis that this is neither accurate nor the best narrative to win over those who are hesitant about vaccines.

Washington instructed the Continental Army soldiers to undergo variolation. In the absence of vaccines, variolation had to be done with smallpox virus and carried significant risks.
Image from wikimedia commons.

The race to produce a coronavirus vaccine seems to have become a matter of national prestige. Recently Russia has claimed to be about to release the first vaccine. No data, though, is available and some fear corners are being cut.

It would make sense to start with coronavirus vaccination for those with the highest risk of death from this infection: the risk-benefit analysis would be tilted heavily towards the benefit of vaccination. Surveillance of side-effects, after the release of a coronavirus vaccine, will bolster confidence to extend the vaccination to lower risk groups.

Although coronavirus vaccines are urgently required, we must not compromise safety: large phase 3 studies and post-marketing surveillance are equally important, and transparency throughout will be necessary to build the necessary public confidence. In addition, the vaccine promotion campaign needs to be carefully thought through, with emphasis on the collective and not just the individual benefits.

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