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Innate immune memory and vaccination: a controlled schedule for improved benefit

A study led by IMVA-HB/IDMIT researchers, published in NPJ Vaccines, has shown the influence of the delay between vaccinations (primary and booster) on the specific humoral immune response. This work also suggests the establishment of a trained immune memory.

Published on 19 March 2020

Vaccines represent one of the greatest successes in medicine, reducing mortality and morbidity associated with many infectious diseases. Thanks to vaccines and effective global vaccination campaigns, pathogens can be eradicated from the planet, as was the case with the smallpox virus in the 1980s, and will be the case in the near future - as hoped for with the polio virus. According to the World Health Organization, vaccinations save the lives of 2 to 3 million people worldwide every year.

However, we still don't have vaccines against certain diseases such as AIDS, and the development of a vaccine is an extremely long process that is ill-suited to deal with emerging diseases.

Vaccine research aims not only to develop new vaccines, but also to improve the comfort, tolerance and efficacy of existing vaccines. It is expected that a better understanding of the mode of action of vaccines that work would allow for a more rational, faster development of new vaccines, improve current vaccination protocols, and personalize vaccinations.

With this goal in mind, a team of vaccinologists from IMVA-HB/IDMIT has analyzed the dynamics of innate and acquired immune responses and their interactions after primary and booster vaccination. To do this, they vaccinated monkeys with a live, highly attenuated vaccine, MVA (Modified Vaccinia Ankara). The model vaccine, MVA, is a vaccine that protects against smallpox and is showing encouraging results as a recombinant vaccination vector against other diseases when it expresses their antigens. Because of their phylogenetic proximity to humans, non-human primates, such as the macaque monkey, provide strong pre-clinical models for studying the immunology of human vaccines.

By comparing different vaccination schedules with a two-month or two-week booster vaccination, they have demonstrated the influence of the delay between vaccinations on the antibody response. While it may be tempting to shorten the vaccination schedule to provide more rapid protection of the population at risk in the event of a public health emergency against a pandemic, an accelerated vaccination schedule has been shown to be detrimental to humoral immunity.

They have also shown that the vaccination schedule also has an impact on innate response. The later booster (at two months) not only improved the specific antibody response of the MVA vaccine, it also involved more activated and mature innate cells as shown by complex phenotypic analysis in mass cytometry. Neutrophils, monocytes and dendritic cells with altered phenotype, better equipped to respond to new stimulation, were induced late after primary vaccination and their abundance correlated positively with antibody concentration and multifunction.

This work suggests the development of an innate immune memory, also called trained immunity1 , which has recently been described for monocytes and NK cells, and whose mechanisms and characteristics differ from the "classical" memory of T and B lymphocytes. This remains to be demonstrated by functional analysis. Most importantly, they reveal the major effect of the delay between immunizations on vaccine response and highlight the link between innate, early but also late response and humoral response.

Vaccines based on trained immunity could combine the induction of innate and adaptive immune memory and thus confer better protection against the pathogen they target, but also against other pathogens, and increase and modulate responses to re-vaccination or new independent vaccinations. This involves identifying vaccines and adjuvants capable of stimulating innate memory and deciphering the underlying mechanisms to better exploit them.

1: Unlike adaptive memory, innate myeloid memory is not antigen-specific. It is carried by monocytes with improved antimicrobial functions against stimuli that have nothing to do with the initial inducing stimulus. Thus, BCG, the canonical stimulus of innate memory, protects more than against tuberculosis. Furthermore, trained immunity does not appear to involve clonal expansion of monocytes and their differentiation into monocyte memory, but metabolic, epigenetic, and transcriptional changes in hematopoietic progenitors/precursors generating trained monocyte progeny.

IMVA-HB, a research infrastructure led by Dr. Roger Le Grand, brings together more than 100 researchers working on scientific challenges related to innate and adaptive immunity in the context of viral infections and the regulation of autoimmune diseases. IMVA-HB is a joint research unit (UMR1184) associating CEA, Inserm and the University of Paris-Saclay and has a strong link with the Pasteur Institute.
This work has been supported by le Programme Investissement d’Avenir at three levels : the Labex Vaccine Research Institute (VRI) (ANR-10-LABX-77-01) by funding the ImMemory research program on the dynamics of innate and acquired responses and their interactions in the context of primary immunization followed by booster vaccination ; the FlowCyTech Equipex (ANR-10-EQPX-02-01) by financing the mass cytometry ; IDMIT Infrastructure of Excellence (ANR-11-INBS-0008) by funding the NHP Animal Facility for the study of infectious diseases.
This work has also been supported by the European Union through the EVHA H2020 (funding n.681032) and TRANSVAC2 H2020 (funding n.730964) projects.

EVHA 2020 


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