While the extent of interaction can be expected to go substantially beyond current knowledge, analysis has shown that gut microbiota are critical for achieving potent immunity using inactivated influenza vaccine s. Toll-like receptor 5 (TLR5)-mediated pathway is critical for vaccine efficacy where gut microbiota provide stimuli for development of plasma cells ultimately impacting antibody production, while live vaccine s and adjuvanted vaccines may not share this dependency. Similarly, the importance of intestinal flora composition has been demonstrated for TLR7-stimulated development of inflammasomes in respiratory mucosa, where lack of TLR7 ligands leads to impaired immune response s to influenza [1,2]. Likewise, it has recently been shown that pathogen -free mice are more sensitive to influenza challenge than other mice and that inflammation can be dampened via colonization with Streptococcus aureus in a TLR2-dependent way [ 3 ]. However, respiratory influenza infection can lead to gastroenteritis-like symptoms not via direct infection of gut epithelia, but rather due to a shift in gut microbiota leading to increase in Th17 cells in the small intestine and also enhanced IL15/IL17A production, an effect abolished by antibiotics [ 4 ]. Possibly adding some detail to this observation, Weber et al. conclude that IL17-producing thymocytes form a “first line of recognition” stimulated by cell wall components of diverse pathogenic and apathogenic bacteria, but that effector molecules such as IL-6 and IFN-γ determine transition to a pathological inflammation [ 5 ]. It has also been demonstrated that microbiota depletion impairs early innate immunity against the pathogen Klebsiella pneumoniae and that this state can be remedied by providing NOD-like (NLR) receptor ligands but not Toll- like receptor (TLR) ligands from the gastrointestinal tract, whereas NLR ligands from the upper respiratory tract were ineffective [ 6 ]. This highlights the systemic impact of local micro biota on immune responses and suggests a critical importance of microbiota derived pattern recognition receptor (PRR) ligands for establishing effective immunity. In summary it can be stated that current evidence shows heavy dependency of microbiota and microbiota composition on activity of the immune system and efficacy of at least some of the vaccines. Bacteria are not the only microorganisms modulating the immune system; the virome can support intestinal homeostasis comparable to bacterial commensals, presumably by providing equivalent stimuli [ 7 , 8 ]. Similarly, fungal diversity and species composition may prove to be a critical extension also in other areas than chronic inflammatory disorders of the gut [ 9 ]. The terrible and disfiguring childhood disease Noma (cancrum oris) is currently thought to be caused by malnutrition and microflora dysbiosis [ 10 ]. There is also clear evidence that the choice of food impacts microbiome development and ultimately immune competence [ 11 ]. The interplay of human nutrition, gut microbiome, immune system development and competence, dysfunction, and vaccine efficacy is the focus of ongoing research and is now viewed as a very likely critical dimension of immunology and hence possibly also vaccinology [ 11 – 17 ]. The impact of micro biota and microbial diversity on vaccine efficacy in infants has recently been investigated in a small cohort by Huda et al. where they suggest probiotics for minimizing dysbiosis [ 18 ]. Of note in this context, while microbiota have emerged as an important immunological dimension, metagenomics has emerged as a powerful tool for analysis of the microbial community in an organism. Metagenomics could be used to identify and quantitate the gut microbiota of the fecal samples. Several other body (especially mucosal) surfaces are commonly covered by microbial communities; within the gastrointestinal system several distinct regions exist which contain microbiota of typically different composition. Moreover, the gel layer and luminal communities of gut microbiota have been shown to feature different population composition [ 19 ]. Finding ways to routinely access these spatial dimensions in health and disease may open yet another possible critical aspect for integration into the growing number of systems components regarding immunity and also vaccine effects. The gut glycome is another uninvestigated area presumably providing substantial immunologically relevant mass to the human body.

The distinction between a commensal and a pathogen can be difficult to draw, depending on the potential to be involved in dis ease. Examples of organism with potential impact on vaccinology are immune-distorting bacteria like Mycoplasma species which can cause diverse diseases in animals and humans [ 20 ] but are also non obvious (and often unidentified) microbes of the natural microbiome [ 20 , 21 ]. As multiple roles have been suggested for the human pathogen M. pneumoniae this may either mean a substantial under- appreciation of other causes of atypical pneumonia or otherwise of other factors contributing to the conversion from an asymptomatic infection to a severe disease. Mycoplasma species are also frequently associated with autoimmune diseases [ 22 ]. The mechanism by which Mycoplasmas modulate the immune system are not clear, and part of the reason is that these pathogens may contribute to a pro-inflammatory or otherwise immunologically biased environment rather than being clear-cut pathogens in the sense of Koch’s postulates. At least in chicken severe exacerbation of otherwise asymptomatic (avian) influenza infection with M. gallisepticum , a Mycoplasma phylogenetically close to M. pneumoniae , has been documented [ 23 ]. Several known interactions exist where these can lead to nonadditive exacerbation of other infections through intensified inflammatory responses. At least in Ureaplasma species the term pseudospecies has been used, as different isolates may vary greatly in their content of pathogenicity factors. In fact, from both a general health and a vaccine perspective it may be equally critical to consider the immuno-modulatory pathogenicity mechanisms available within a person’s microbiome along with specific bacterial species, as their combined effect may be very distinct or at least nonadditively amplified from individual factor contributions [ 24 ].

Another example of frequently observed chronic pathogen includes the highly prevalent immune distorting viruses of genus lymphocryptovirus comprising Epstein - Barr virus ( EBV ) and Cytomegalovirus ( CMV ); these cause lifelong infections, and EBV is known for its B-cell tropism. Both viruses can establish regulatory complex periods of latency. The effect of EBV and CMV infection versus age on immunity has recently been studied by Wang et al. where they differentiated age-dependent and -independent effects [ 25 ]. Specifically, decreased diversity of antibody repertoires with accumulation of memory B-cells and lower naive B-cell populations was associated with reduced vaccine efficacy in the elderly. They report that immune-globulin heavy chain (IGHV) mutation frequency increases upon infection with CMV , but not EBV. CMV infection tends to increase the proportion of highly mutated IgG and IgM regions, but not IgA or IgD. The effect of CMV on mutation rate is stronger with age, where the effect may stem from the proportion of CMV -specific clones. Age and EBV infection correlated with persistent clonal expansion, where very few clonal lineages (possibly derived from a single ancestor) tend to be over represented. In the study these expanded clones may be cases of monoclonal B-cell lymphocytosis (MBL), a lymphoproliferative disorder with some characteristics of CLL typically seen in the elderly.

The inflammatory status including degree of immune system activation can have significant impact on vaccine efficacy. Recently it was shown in a YF-17D (yellow fever vaccine) trial comparing vaccination efficacy of 50 volunteers in Lausanne (Switzerland) versus the same number in Entebbe (Uganda) that the latter produced less effective humoral and CD8 + responses. The authors negatively correlated the pre-existing activation level of CD8 + T-cells and B-cells as well as pro-inflammatory monocytes at the time of vaccination with this reduced response [ 26 ]. Admittedly it would also be interesting to know the cause of this inflammation, as the specific reason may affect the impact on vaccines. On the other hand the impact of pre-existing low-grade inflammatory conditions on vaccines is a recurring theme in the current review. In this context it is evident that determining protectivity profiles for vaccines is only one side of the coin. The other one is that the status of the vaccine recipient regarding inflammatory diseases, nutrition, and pre-existing immunity needs to be considered to understand inter-patient variability. Unfortunately the complex interaction of multiple clinical and subclinical infections is poorly understood. In the context of vaccines, inflammation and potential impact of chronically infecting pathogens and pathogen interactions need to be addressed.

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مواضيع ذات صلة

Vaccines and the Role of Pre-existing Immunity

Examples of Protein Subunit Vaccines

Methods for Using Full-Length Antigens (Proteins) as Vaccines

Pan-Genomic Analysis

Reverse Vaccinology

Improving Vaccines over Natural Immune Responses

Selecting Vaccine Antigens

Principles of Vaccine Development

A Brief History of Vaccination

Development of Vaccines for Tuberculosis and Meningitis

Development of Vaccines for Viral Hepatitis, Coronavirus, and Norovirus

Development of Powerful Influenza Vaccines