Trends in Immunology
Volume 34, Issue 9, September 2013, Pages 431-439
Journal home page for Trends in Immunology

Review
A small jab – a big effect: nonspecific immunomodulation by vaccines

https://doi.org/10.1016/j.it.2013.04.004Get rights and content

Highlights

  • Routine vaccines may alter resistance to unrelated pathogens in children.

  • Live vaccines are associated with increased protection to other pathogens.

  • Inactivated vaccines may increase susceptibility to other pathogens.

  • ‘Heterologous immunity’ and ‘trained innate immunity’ may explain these effects.

Recent epidemiological studies have shown that, in addition to disease-specific effects, vaccines against infectious diseases have nonspecific effects on the ability of the immune system to handle other pathogens. For instance, in randomized trials tuberculosis and measles vaccines are associated with a substantial reduction in overall child mortality, which cannot be explained by prevention of the target disease. New research suggests that the nonspecific effects of vaccines are related to cross-reactivity of the adaptive immune system with unrelated pathogens, and to training of the innate immune system through epigenetic reprogramming. Hence, epidemiological findings are backed by immunological data. This generates a new understanding of the immune system and about how it can be modulated by vaccines to impact the general resistance to disease.

Section snippets

Vaccines against infectious diseases

By definition, ‘A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and ‘remember’ it, so that the immune system can more easily recognize and destroy any of these microorganisms

Measles vaccine

Standard titer measles vaccine is recommended at 9 months of age in low-income countries where measles infection is endemic and often fatal. Many observational studies have shown that measles-vaccinated children have substantially lower mortality than can be explained by the prevention of measles-related deaths, for reviews, see 5, 15. Observational studies are obviously prone to selection bias, and beneficial effects are to be expected if it is the healthiest children who are vaccinated.

Immunological evidence for nonspecific effects of vaccines

As reviewed above, although epidemiological evidence for nonspecific effects of vaccines is accumulating, more recently from randomized trials, the perceived lack of biological plausibility has been a major obstacle in recognizing and further investigating these effects. Hence, it is important to consider immunological mechanisms that may mediate such effects.

Below, we describe how novel insights in understanding the adaptive immune system and innate immunity provide arguments that state

A new paradigm: vaccines modulate general resistance

The epidemiological data indicate that vaccines have nonspecific effects that may be just as important or even more important for childhood survival than their specific effects [4]. Existing studies suggest a general pattern, namely that the live vaccines: BCG, measles vaccine, and Vaccinia are associated with beneficial nonspecific effects, leading to reduced all-cause mortality, whereas the inactivated, alum-adjuvated DTP vaccine is associated with increased susceptibility to other unrelated

Paradigms and dogmas: why have these effects been overlooked?

If vaccines can modulate the immune system in a more general way, as suggested by epidemiological and immunological data, it opens an avenue to a new understanding of the immune system as a learning system. Just like the brain, the immune system seems to extend what has been learned in one context to new contexts. In the brain it is known that inference takes place, because of the obvious mismatch between the sparse information provided by our senses and the strong generalizations and powerful

Concluding remarks

Nonspecific effects of vaccines have been dismissed or ignored because they are difficult to explain biologically. However, the nonspecific effects of vaccines are reproducible in randomized controlled trials [88] and the potential implications merit further investigations. The new evidence that vaccines induces cross-reactivity and train the innate immune system, and that these effects can be beneficial and detrimental, provides biological support for the epidemiological findings. In our

Acknowledgments

M.G.N. was supported by a Vici Grant of The Netherlands Organization for Scientific Research (NWO). C.S.B. was supported by an ERC Starting Grant (ERC-2009-StG-243149). P.A. holds a professorship from Novo Nordisk Foundation. The Research Center for Vitamins and Vaccines (CVIVA) is funded by the Danish National Research Foundation (DNRF108).

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