Human lymph node immune dynamics as driver of vaccine efficacy: an understudied aspect of immune responses

ABSTRACT

Introduction

During the last century, changes in hygiene, sanitation, and the advent of childhood vaccination have resulted in profound reductions in mortality from infectious diseases. Despite this success, infectious diseases remain an enigmatic public health threat, where effective vaccines for influenza, human immunodeficiency virus (HIV), tuberculosis, and malaria, among others remain elusive.

Area covered

In addition to the immune evasion tactics employed by complex pathogens, our understanding of immunopathogenesis and the development of effective vaccines is also complexified by the inherent variability of human immune responses. Lymph nodes (LNs) are the anatomical sites where B cell responses develop. An important, but understudied component of immune response complexity is variation in LN immune dynamics and in particular variation in germinal center follicular helper T cells (Tfh) and B cells which can be impacted by genetic variation, aging, the microbiome and chronic infection.

Expert opinion

We describe the contribution of genetic variation, aging, microbiome and chronic infection on LN immune dynamics and associated Tfh responses and offers perspective on how inclusion of LN immune subset and cytoarchitecture analyses, along with peripheral blood biomarkers can supplement systems vaccinology or immunology approaches for the development of vaccines or other interventions to prevent infectious diseases.

KEYWORDS:

• Lymph nodes
• vaccination
• Tfh
• adaptive immunity
• immune variation

Article highlights

• Vaccination has led to significant improvements in morbidity and mortality indices over the past decades, especially amongst infants and in adults

• Effective vaccines for complex pathogens such as influenza, HIV, tuberculosis, and malaria, remain elusive.

• The inherent variability of human immune responses complexifies our understanding of immunopathogenesis and the development of effective vaccines. An important, but understudied component of this complexity is variation in lymph node immune dynamics and in particular variation in germinal center follicular helper T cells (Tfh) and B cells which can be impacted by genetic variation, aging, the microbiome and chronic infection.

• Histopathological and high-dimensional in situ analysis of innate and adaptive tissue resident immune phenotypes, in conjunction with genetic, transcriptomic and microbiome network analysis can inform about the mechanistic drivers of immune system variation and accelerate the development of new vaccines by establishing clear LN-specific mechanistic targets.

List of Abbreviations

AE Adverse Event

AIDS Acquired Immunodeficiency Syndrome

BAFF B cell activating Factor

BCR B cell Receptor

CMV Cytomegalovirus

DC Dendritic cell

DZDark Zone

FDCFollicular Dendritic Cell

FNA Fine-Needle Aspiration

FRCFibroblastic Reticular Cell

GALT Gut-Associated Lymphoid Tissues

GCGerminal Center

HBVHepatitis B Virus

HEVHigh Endothelial Venules

HIVHuman Immunodeficiency Virus

LN Lymph Node

LPSLipopolysaccharide

LZLight Zone

MBLMannose-Binding Lectin

MCMVMurine Cytomegalovirus

MoDCmonocyte-derived Dendritic Cell

NHPNon-Human Primate

pMHCpeptide- Major Histocompatibility Complex

RNARibonucleic Acid

SNP Single Nucleotide Polymorphism

Tfh Follicular helper T cells

TLRToll-Like Receptor

Declaration of interest

R M. Paris is employed by Moderna. Moderna had no role in the design, analysis or preparation of this manuscript. All other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author Contributions

All authors substantially contributed to the conception and design of the review article, the interpretation of the relevant literature and were involved in writing the review article or revising it for intellectual content.

Additional information

Funding

This research was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health, and a Bill and Melinda Gates Foundation (# OPP1147555) CAVD grant (# OP1032325).