Elsevier

Clinical Therapeutics

Volume 35, Issue 2, February 2013, Pages 109-114
Clinical Therapeutics

Youth and children: Vaccines update
Commentary
Nonspecific Effects of Vaccines and the Reduction of Mortality in Children

https://doi.org/10.1016/j.clinthera.2013.01.007Get rights and content

Abstract

There is now strong evidence that vaccines have substantial nonspecific (heterologous) effects in children in high-mortality regions. The hypothesis states that, until a different vaccine is given: (1) live vaccines induce a protective nonspecific immune response, whereas inactivate vaccines cause a harmful nonspecific immune response; (2) Bacillus Calmette-Guerin (BCG) vaccine approximately halves mortality from infections other than tuberculosis; (3) provided vitamin A was not given at birth, measles vaccine approximately halves mortality from infections other than measles (this effect may be stronger if the child still has maternal antibody); and (4) whole-cell diphtheria-tetanus-pertussis (DTP) vaccine increases mortality from infections other than diphtheria, tetanus, and pertussis (this effect is stronger in girls than boys). These observations suggest that minor modifications to the routine immunization schedule could reduce child mortality by at least 30%, and they have important implications for the design of randomized trials of vaccines in high-mortality regions.

Introduction

There is now strong evidence that vaccines have substantial nonspecific (heterologous) effects in children in high-mortality regions.1, 2 The first major study suggesting that vaccines have important nonspecific effects was published >11 years ago.3 This large cohort study from Guinea-Bissau in West Africa concluded that whole-cell diphtheria-tetanus-pertussis (DTP) vaccine may increase mortality—a finding that caused considerable controversy. Over the subsequent decade, many more observational studies were published, with conflicting results.1, 4 However, analysis of data from observational studies of this issue is particularly difficult due to the potential for survival bias (which favors immunization) and because nonvaccinated children in observational studies from high-mortality regions tend to be disadvantaged, with an increased risk of death (which causes selection bias in favor of immunization).2, 4, 5 Consequently, the World Health Organization (WHO) concluded in 2008 that conclusive evidence about the nonspecific effects of vaccines is unlikely to be obtained from observational studies.6 Fortunately, we now have a substantial body of evidence from randomized controlled trials (RCTs) and it supports the hypothesis that, until the next vaccine is given, Bacillus Calmette-Guerin (BCG) and measles vaccines have potent beneficial nonspecific effects (Table).1, 7, 8, 9, 10, 11, 12, 13

Section snippets

BCG Vaccine

In 6 controlled trials from the United States and the United Kingdom in the 1940–1950s, the mortality rate ratio (95% CI) for diseases other than tuberculosis (TB) was 0.75 (0.59–0.94) for BCG versus control (Table [line 1]).1

A randomized trial from Guinea-Bissau reported that, among children who had received a booster dose of DTP at 18 months, the mortality rate ratio after BCG was 0.36 (0.13–0.99) compared with controls (Table [line 2]).9

Two trials of similar design from Guinea-Bissau tested

Measles Vaccine

In Gambia, Guinea-Bissau, Senegal, and the Sudan, the mortality rate ratio (95% CI) has been reported to be 0.53 (0.37–0.77) in girls randomly assigned to receive measles vaccine at 9 months of age (Table [line 4]).1 Girls in the control group had been immunized against measles at 5 months of age; so, the difference was not due to reduced mortality from measles.

In another study, provided vitamin A had not been given at birth, children in Guinea-Bissau who were randomly assigned to receive an

DTP Vaccine

No randomized trials are available on the effect of DTP on all-cause mortality. Although WHO will accept evidence only from RCTs,6 it has also stated that it would be unethical to conduct an RCT of DTP vaccine. However, subset analyses of the data from RCTs of BCG strongly suggest that DTP increases mortality, especially in girls.2

In the RCT of revaccination with BCG at 19 months of age (BCG2) in Guinea-Bissau (Table [line 2]),9 60% of the participants had not received a booster dose of DTP

Evidence of Nonspecific Effects

Evidence of the nonspecific effects of vaccines comes from 18 countries. The randomized trials were from the Gambia, Guinea-Bissau, Senegal, Sudan, the United Kingdom, and the United States (Table), and the observational studies were from Bangladesh, Benin, Burkina Faso, Burundi, Ghana, Guinea-Bissau, Haiti, India, Malawi, New Guinea, the Philippines, Senegal, and Zaire.1, 21, 22

Recent evidence suggests that BCG confers nonspecific protection through an epigenetic effect on innate immunity

Expanded Programme on Immunization Schedule

In many low-income countries, the Expanded Programme on Immunization (EPI) vaccines target tuberculosis, polio, diphtheria, tetanus, pertussis, and measles, but these are not the leading causes of death in children, even in nonimmunized communities.28 The main reason that the EPI program has been beneficial may not be because it protects against these infections but because the nonspecific effects of the BCG and measles vaccines reduce the very large number of deaths from pneumonia and sepsis,

Conclusion

The available evidence suggests that minor modifications to the routine immunization schedule could reduce child mortality by at least 30%, and has important implications for the design of randomized trials of vaccines in high-mortality regions.

Conflict of Interest

The author has indicated that he has no conflicts of interest regarding the content of this article.

Acknowledgment

Dr. Shann was solely responsible for the literature search, data interpretation, and writing of the manuscript.

References (31)

  • S. Biering-Sorensen et al.

    Small randomized trial among low-birth-weight children of Bacillus Calmette-Guerin vaccination at first health center contact

    Pediatr Infect Dis J

    (2012)
  • A. Roth et al.

    Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau

    BMJ

    (2010)
  • P. Aaby et al.

    Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial

    BMJ

    (2010)
  • P. Aaby et al.

    Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial

    Arch Dis Child

    (2012)
  • P. Aaby et al.

    The introduction of diphtheria-tetanus-pertussis vaccine and child mortality in rural Guinea-Bissau: an observational study

    Int J Epidemiol

    (2004)
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