Youth and children: Vaccines updateCommentaryNonspecific Effects of Vaccines and the Reduction of Mortality in Children
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.
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