Elsevier

Vaccine

Volume 34, Issue 34, 25 July 2016, Pages 3923-3930
Vaccine

Conference report
Heterologous vaccine effects

https://doi.org/10.1016/j.vaccine.2016.06.020Get rights and content

Abstract

The heterologous or non-specific effects (NSEs) of vaccines, at times defined as “off-target effects” suggest that they can affect the immune response to organisms other than their pathogen-specific intended purpose. These NSEs have been the subject of clinical, immunological and epidemiological studies and are increasingly recognized as an important biological process by a growing group of immunologists and epidemiologists. Much remain to be learned about the extent and underlying mechanisms for these effects.

The conference “Off-target effects of vaccination” held in Annecy-France (June 8–10 2015) intended to take a holistic approach drawing from the fields of immunology, systems biology, epidemiology, bioinformatics, public health and regulatory science to address fundamental questions of immunological mechanisms, as well as translational questions about vaccines NSEs. NSE observations were examined using case-studies on live attenuated vaccines and non-live vaccines followed by discussion of studies of possible biological mechanisms. Some possible pathways forward in the study of vaccines NSE were identified and discussed by the expert group.

Introduction

Our understanding of the immunological landscape is changing dramatically. We now know that immune memory can be re-educated, that innate immunity can have “memory,” that certain lymphocytes can exhibit innate-like responses, and that vaccines may have broader specificities that vary with age and sex. Classical immunology is being recast as we go from murine immunology to human immunology and as big data is stored, curated and investigated. Clinical, immunological and epidemiological studies appear to demonstrate that vaccines can affect the immune response to organisms other than their pathogen-specific intended purpose. For example, Bacille Calmette-Guerin (BCG), smallpox, measles, oral polio and yellow fever vaccines may reduce disease and/or mortality from infections other than tuberculosis, smallpox, measles, polio, yellow fever, respectively, and some vaccines have even shown promise when repurposed against certain cancers and/or autoimmune disorders. These heterologous or non-specific effects (NSEs) of vaccines, occasionally also termed “off-target effects”, suggest that some vaccines can provide greater protection than their pathogen-specific intended purpose.

To examine vaccines NSEs, the Fondation Mérieux organized a conference from June 8–10 2015 entitled: “Off-target effects of vaccination” in Annecy, France (“Les Pensières” Conference Centre). The types of questions about NSEs considered at the workshop were:

  • How does trained immunity (innate immune memory) influence the NSEs of vaccination?

  • How does vaccine-induced NSE immunity vary with age and sex?

  • What is the role of inter-pathogen cross-reactivity in the NSEs of vaccines?

  • How do environmental antigens (such as the microbiome) influence cross-reactivity?

  • Are there negative NSEs?

In addition to addressing fundamental questions of immunological mechanisms, the workshop considered the following translational questions:

  • How does understanding the NSEs/trained immunity change our view of host defence and immunological memory?

  • Could NSEs lead to defining a new class of vaccines, or repurpose existing ones?

  • What is the best way to determine whether the NSEs are real and important or whether their practical implications are minor? What data would be required (immunological, clinical, epidemiological, other) in order to assess the causal relationship?

  • How could these “off label” observations be used to obtain new “on label” indications?

The intent of the workshop was to take a holistic approach to these questions, drawing from the fields of immunology, systems biology, epidemiology, bioinformatics, public health and regulatory science. The workshop was designed to not only advance the science of vaccinology, but also to consider the implications of verified NSEs: how could these previously underappreciated effects be utilized, and what would such an effort entail? The conference assessed the gaps in our knowledge and proposed an agenda for research.

This report provides a summary of the issues discussed, and the key findings and areas for future research and development.

Section snippets

Defining the scope of NSEs: Case studies

The hypothesis that vaccines have NSEs in addition to their actions against their targeted pathogens can be illustrated by studies that evaluated the impact on mortality of measles immunization in young children in West Africa [1], [2] as well as the therapeutic effects of BCG on bladder cancer [3]. Nevertheless, major controversies remain. In 2012–2014, the Strategic Advisory Group of Experts (SAGE) on immunization requested that the World Health Organization (WHO) review the evidence

Basic biological mechanisms

Much remains to be learned regarding the mechanisms by which certain live attenuated vaccines could potentially reduce all-cause mortality. Immunological studies might elucidate the mechanisms by which NSEs occur, confirm their relative importance, and provide a guide to which randomized trials are likely to be most informative and confirmatory. Potential mechanisms for beneficial vaccine NSEs may include: (a) modulation (enhancement) of type 1 and type 17 T helper (Th1, Th17) cells, memory CD4

Resolving NSEs of vaccinations

As reported above, there is growing evidence that vaccines may affect mortality from causes other than the disease for which they were developed and vaccine NSEs are now recognized by a growing number of immunologists and epidemiologists [40], [48]. However, the topic of NSEs of vaccines is contentious, with much of the evidence coming from one country (Guinea Bissau). Accordingly, greater insight is needed, as discussed next. Different trial types may be considered to build the needed

The way forward

A growing body of research in the field of vaccinology suggests that certain vaccines may have heterologous or non-specific effects. As an example, major reductions in all-cause mortality have been consistently noted in observational studies of MV, OPV and BCG, and in randomized trials their NSEs on reducing mortality have been 26% for MV, 32% for OPV and 41% for BCG [22], [11], [33]. Similar effects have also been noted for hospital admission patterns in a high-income setting [6]. However,

Conflict of interest

MG and WLW are employee of Sanofi Pasteur. Other authors declare that they have no conflicts of interest to report.

Acknowledgements

The authors express their gratitude to all speakers who shared their findings. Thanks are also due to Cindy Grasso (meeting coordinator) and the staff of the Mérieux Foundation conference center for outstanding local organization. The organization of this meeting was made possible through support from Sanofi Pasteur.

MGN was supported by an ERC Consolidator Grant (#310372).

OL’s laboratory is supported by Global Health (OPPGH5284) and Grand Challenges Explorations (OPP1035192) awards from the

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