Non-specific effects of vaccines…and their neglect

Author: Nils Skajaa

After implementing a measles vaccination (MV) campaign in 1979 in Guinea-Bissau–a newly-liberated low-income West African country–Peter Aaby and colleagues found that MV-vaccinated children had a 70% lower mortality rate than did MV-unvaccinated children. One might infer this as obvious considering that measles can be fatal. But World Health Organization (WHO) estimates suggested that only about 10% of all deaths were due to measles at the time. How could the mortality rate be 70% lower in MV-vaccinated children compared with MV-unvaccinated children if only 10% of deaths were due to measles? It was an enigma–and to a large extent, it still is.

Bandim Health Project–started by Aaby; now affiliated with Statens Serum Institut, Denmark–is a health and demographic surveillance system site in Guinea-Bissau that follows more than 200,000 individuals on a regular basis in both urban and rural settings. This setting is unique as it permits longitudinal surveillance of real-life interventions such as inmunization programmes.

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Photo: Novo Nordisk Fonden, Bandim Health Project


Since the enigma of the MV in the late 70s, many more vaccines have been added to the routine immunization schedule in Guinea-Bissau and subsequently tested for their real-life effects on overall health. A remarkable yet surprising pattern has emerged: live-vaccines–such as MV, oral polio vaccine, the Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis, and smallpox vaccine–protect against morbidity and mortality more than what would be expected through their disease-specific protection. On the other hand, worryingly, non-live vaccines–such as diphtheria-tetanus-pertussis (DTP) vaccine, H1N1-influenza vaccine, inactivated polio vaccine, and a new malaria vaccine–have consistently been associated with higher morbidity and mortality, despite their disease-specific efficacy. Intriguingly, all available evidence suggests that this effect differs by sex assigned at birth: girls have a two-fold higher mortality rate than do boys following a non-live vaccination.

Preparation of measles vaccine at the Tirana Institute of Hygiene and Epidemiology, by D. Henrioud, 1973. 

At this point, I imagine someone thinking, “surely, vaccines must be tested for their effect on overall health”. But the reality is that while vaccines go through a rigorous regulatory process, at no point in this process are they tested for how they affect overall health; the focus is merely on how well they protect against the target disease and on rare side effects, typically only evaluated in the first weeks following vaccination. The WHO defines a vaccine as “a biological preparation that improves immunity to a particular disease”. Assuming this definition, if a vaccine only has an effect on a particular disease, why should its effects on overall health be tested?

In 2014, the WHO commissioned a systematic review of the available evidence regarding these non-specific effects of vaccines, as they are dubbed. The review focused on BCG, DTP, and MV and concluded that, “BCG and MV reduce overall mortality by more than would be expected through their effects on the diseases they prevent, and receipt of DTP may be associated with an increase in all-cause mortality.

The hesitancy toward the associations found for DTP originated, largely, from the lack of randomized controlled trials. But it is unlikely that such trials be conducted because depriving a child of an already implemented and widely accepted vaccine is considered highly unethical. We must, therefore, rely on well-conducted observational studies to assess these real-life effects. And despite the inherent limitations of observational studies, all known biases favor the vaccinated children (sometimes called “healthy vaccinee bias”) so the finding that a vaccine is associated with increased mortality is to be taken as a real danger signal. That said, most studies originated from resource-poor settings with high child mortality rates. Thus, the effect sizes are not necessarily applicable to all settings globally.

While the WHO review acknowledged the non-specific effects of BCG and MV, it did not recommend any change to the current immunization program. Currently, the immunization schedule in most low-income countries includes receipt of BCG and OPV at birth, three doses of DTP and OPV at 6, 10, 14 weeks of age, and MV at 9 months. The vaccination sequence is important because the non-specific effects of a given vaccine are most pronounced for the most recent vaccine. For example, if a live vaccine is given after a non-live vaccine, evidence suggests that the detrimental non-specific effects of the non-live vaccine are reduced. It would therefore be logical to re-think the structure of the immunization schedule to optimize both the specific and non-specific effects.

According to WHO estimates, vaccines prevent 2–3 million annual deaths. A recent report estimated that a simple tweak to the current immunization schedule in low-income countries may prevent a further 1.5 million (30%) of the total 4.8 million annual deaths of children under 5 years of age. Unfortunately, little change has occurred in global immunization schedules since the start of Bandim Health Project 40 years ago.

One can only speculate about why the research on non-specific effects has been met with an astounding “sound of silence”. Vaccine research is hampered by the toxic dichotomy in public opinion about the safety of vaccines. Dichotomies are rarely beneficial. As with many lifesaving interventions, the reality about vaccines is complex and nuanced. Simplifying it to two poles is devastating for science–supposedly a truth-seeking endeavor.

We, public health professionals, cannot let these groundbreaking yet uncomfortable findings go unheard. Soon the European Medicines Agency-approved non-live RTS,S malaria vaccine is due to be rolled out in Ghana, Kenya, and Malawi. Results from the phase-III trial, conducted by GlaxoSmithKline, the producer, showed that girls receiving the malaria vaccine have a two-fold higher mortality rate than girls not receiving the vaccine. One can only pray that the local monitoring systems in the three African countries can adequately reveal this sex-discrepancy in a real-life setting. If not, the roll-out may have disastrous repercussions.

Nils Skajaa interned at Bandim Health Project during his second year of his MSc in Global Health at the University of Copenhagen. Continuing his work from the internship, he is now writing his thesis.

Further reading:

Bandim Health Project 40-year anniversary book

Sabra L. Klein, Frank Shann, William J. Moss, Christine S. Benn, and Peter Aaby; RTS,S and increased female mortality

TEDx talk by Christine Stabell Benn





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