Trends in Immunology
ReviewA small jab – a big effect: nonspecific immunomodulation by vaccines
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).
References (94)
Vaccinia scars associated with better survival for adults. An observational study from Guinea-Bissau
Vaccine
(2006)Trained immunity: a memory for innate host defense
Cell Host Microbe
(2011)The new decade of vaccines – Authors’ reply
Lancet
(2012)Smallpox vaccination and risk of allergy and asthma
J. Allergy Clin. Immunol.
(2003)Inverse association between melanoma and previous vaccinations against tuberculosis and smallpox: results of the FEBIM study
J. Invest. Dermatol.
(2002)Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: reanalysis of West African studies
Lancet
(2003)Effect of infant immunisation on childhood mortality in rural Bangladesh: analysis of health and demographic surveillance data
Lancet
(2004)Specific history of heterologous virus infections determines anti-viral immunity and immunopathology in the lung
Am. J. Pathol.
(2003)Pathological features of heterologous immunity are regulated by the private specificities of the immune repertoire
Am. J. Pathol.
(2010)Attrition of T cell memory: selective loss of LCMV epitope-specific memory CD8 T cells following infections with heterologous viruses
Immunity
(1999)
Virus-specific CD4+ memory-phenotype T cells are abundant in unexposed adults
Immunity
Erythema nodosum provoked by hepatitis B vaccine
Lancet
Quadrivalent Human Papillomavirus recombinant vaccine associated lipoatrophy
Vaccine
Pathogen recognition and innate immunity
Cell
Macrophage receptors implicated in the “adaptive” form of innate immunity
Microbes Infect.
Maternal transfer of strain-specific immunity in an invertebrate
Curr. Biol.
Does chromatin remodeling mark systemic acquired resistance?
Trends Plant Sci.
Molecular aspects of defence priming
Trends Plant Sci.
Protective immunity induced by low-virulence Candida albicans: cytokine production in the development of the anti-infectious state
Cell. Immunol.
Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes
Cell Host Microbe
Taking advantage of the positive side-effects of smallpox vaccination
J. Vet. Med. B: Infect. Dis. Vet. Public Health
Sex-specific differences in mortality after high-titre measles immunization in rural Senegal
Bull. World Health Organ.
Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial
BMJ
The optimal age of measles immunisation in low-income countries: a secondary analysis of the assumptions underlying the current policy
BMJ Open
Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?
J. Infect. Dis.
Small randomized trial among low-birth-weight children receiving bacillus Calmette–Guerin vaccination at first health center contact
Pediatr. Infect. Dis. J.
Smallpox vaccination and all-cause infectious disease hospitalization: a Danish register-based cohort study
Int. J. Epidemiol.
Vaccinia scars associated with improved survival among adults in rural Guinea-Bissau
PLoS ONE
Testing the hypothesis that diphtheria-tetanus-pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries
BMJ Open
Bacille Calmette–Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes
Proc. Natl. Acad. Sci. U.S.A.
No one is naive: the significance of heterologous T-cell immunity
Nat. Rev. Immunol.
Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries
BMJ
Do childhood vaccines have non-specific effects on mortality?
Bull. World Health Organ.
Do measles vaccines have non-specific effects on mortality?
Bull. World Health Organ.
Bacillus Calmette–Guerin vaccination and infant mortality
Expert Rev. Vaccines
The non-specific effects of vaccines
Arch. Dis. Child.
Bacille–Calmette–Guerin vaccination and the development of allergic disease in children: a randomized, prospective, single-blind study
Clin. Exp. Allergy
Non-specific effects of BCG?
J. Infect. Dis.
The introduction of diphtheria-tetanus-pertussis vaccine and child mortality in rural Guinea-Bissau: an observational study
Int. J. Epidemiol.
Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa
BMJ
Evaluation of non-specific effects of infant immunizations on early infant mortality in a southern Indian population
Trop. Med. Int. Health
Non-specific effects of vaccination on child survival: prospective cohort study in Burkina Faso
BMJ
Non-specific effects of vaccination on child survival? A prospective study in Senegal
Trop. Med. Int. Health
Benefits of routine immunizations on childhood survival in Tari, Southern Highlands Province, Papua New Guinea
Int. J. Epidemiol.
Editorial: ‘Non-specific effects of vaccines’- an important analytical insight, and call for a workshop
Trop. Med. Int. Health
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