Clin Infect Dis. 2013 Jul;57(2):283-9.

Heterologous (“nonspecific”) and sex-differential effects of vaccines: epidemiology, clinical trials, and emerging immunologic mechanisms.

Flanagan KL, van Crevel R, Curtis N, Shann F, Levy O; Optimmunize Network.

Monash University, Melbourne, Australia.



A growing body of evidence from epidemiologic, clinical, and immunologic studies indicates that vaccines can influence morbidity and mortality independent of vaccine-specific B-cell or T-cell immunity. For example, the live attenuated measles vaccine and BCG vaccine may reduce mortality from infections other than measles or tuberculosis, respectively. Immunologists call these heterologous effects and epidemiologists have called them nonspecific effects, indicating that they manifest against a broad range of pathogens/disease. These effects differ by sex, can be beneficial or detrimental, and appear to be mediated by mechanisms including innate immune memory (also known as “trained immunity”) and cross-reacting lymphocytes. Herein we review recent studies in this emerging field based on a meeting of experts, the recent Optimmunize meeting, held in Copenhagen, Denmark, in August 2012. Further characterization of these effects is likely to expand the way vaccines are evaluated and alter the manner and sequence in which they are given.

KEYWORDS: heterologous effects, innate immunity, nonspecific effects, sex-differential effects, vaccine

PMID: 23572484




A growing number of randomized trials and observational studies suggest that some vaccines influence morbidity and mortality independent of vaccine-specific B-cell or T-cell immunity. Immunologists refer to these as heterologous effects (HE) and epidemiologists call them non-specific effects. Some of these HE are beneficial, and thus might be exploited further; while others may be detrimental, depending on the sex of the recipient and the timing and sequence of vaccination. A group of international experts involved in epidemiological or laboratory studies relevant to vaccine HE formed a consortium called “Optimmunize” in 2010 [1]. A meeting was held by the group in August 2012 in Copenhagen, Denmark, to discuss the latest epidemiological evidence, and progress in elucidating the immunological mechanisms for vaccine HE.

A New Paradigm in Vaccinology

The current paradigm holds that vaccines protect only against the target disease, with equivalent effects regardless of the order in which vaccines are given, sex of the recipient, season, or other variables. Accordingly, the major priority is securing 100% vaccination coverage. An alternative paradigm considers the immune system to be uniquely influenced by each vaccine given. In this model, vaccines have HE that influence the immune response to subsequent unrelated stimuli. These HE are influenced by the type of vaccine and the sequence of vaccination, they differ in males and females, and when micronutrients are co-administered.

Paper Overview

This paper reviews the epidemiological evidence for the HE of vaccines, and evidence that vitamin A supplementation enhances these effects. The results of a randomized controlled trial (RCT) of neonatal BCG vaccination in Guinea-Bissau are discussed which showed a 45% (95% CI 11-66%) decrease in mortality in the first 4 weeks of life [2], due to reduced cases of sepsis and respiratory infections [3]. Another RCT showed that measles vaccination (MV) at 4½ months of age, in addition to the usual 9 month vaccination, led to a 41% (95% CI 11-61%) decrease in all-cause mortality from 4.5 to 36 months of age in children in Guinea-Bissau [4]. In contrast, diphtheria, tetanus and whole-cell pertussis vaccine (DTwP), though protective against the target diseases, is associated with increased total child mortality, especially in females [5, 6]. Overall, studies evaluating the effects of vaccination on infant and child mortality suggest several patterns: a) potentially beneficial HE with live vaccines such as BCG and MV; b) potentially detrimental HE with certain inactivated vaccines such as DTwP; c) the order of vaccination can be important [5]; and d) HE appear to be stronger in females than males.

Features of the immune system of neonates and infants are described, in particular the fact that they are Th2 and Th17 biased [7], with plasma containing multiple immune regulatory factors [8]. Evidence that BCG vaccination can result in epigenetic enhancement of innate immune responses to unrelated pathogens is discussed [9], raising the possibility that epigenetic modification may account for the HE of vaccines. The data and potential mechanisms supporting sex differences in vaccine immunity are discussed, which support the observation that susceptibility to HE varies by sex. The role that induction of cross-reactive adaptive immunity, also called heterologous immunity, might play in HE of vaccines is reviewed [10]. Finally, the effect of geographic location on immune responses and urban / rural differences in immunity are discussed as potential confounding factors in studies of vaccines.


The growing body of evidence supporting vaccine HE has major implications for basic and translational vaccine research, and may eventually guide vaccine policy. The “Optimmunize” group concluded that basic, translational and clinical studies of vaccine HE and their sex-differential nature are major research priorities. State-of-the-art tools to investigate the immune system, including transcriptomics, metabolomics, tissue engineering, microbiomics, epigenomics, multi-parameter flow cytometry and phospho-signalling should be used to elucidate underlying biological mechanisms. Independent replication of the RCTs from West Africa is a high priority, and should take every opportunity to characterize immunologic mechanisms. A group of experts at WHO have recently conducted a systematic review of the literature pertaining to the HE of vaccines, the results of which will be published shortly.

Characterizing the mechanisms underlying vaccine HE should not only enable reduction of any potentially untoward vaccine HE, but also allow beneficial HE to be harnessed through deliberate, timed and targeted immune modulation. Hence, we may be able optimize vaccine schedules and thereby substantially enhance the benefits provided by immunization programs, potentially resulting in further dramatic reductions in child mortality.


The Second “Optimmunize” Meeting was funded by the Novo Nordisk Foundation, Denmark and by the Danish National Research Foundation (DNRF108). The authors declare no known conflicts of interest.


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9.            Kleinnijenhuis J, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci USA 2012; 109:17537–17542.

10.          Selin LK, et al. Heterologous immunity: immunopathology, autoimmunity and protection during viral infections. Autoimmunity 2011; 44:328–347.


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