Impact of Microbiota: A Paradigm for Evolving Herd Immunity against Viral Diseases.

Herd immunity is the most critical and essential prophylactic intervention that delivers protection against infectious diseases at both the individual and community level. This process of natural vaccination is immensely pertinent to the current context of a pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection around the globe. The conventional idea of herd immunity is based on efficient transmission of pathogens and developing natural immunity within a population. This is entirely encouraging while fighting against any disease in pandemic circumstances. A spatial community is occupied by people having variable resistance capacity against a pathogen. Protection efficacy against once very common diseases like smallpox, poliovirus or measles has been possible only because of either natural vaccination through contagious infections or expanded immunization programs among communities. This has led to achieving herd immunity in some cohorts. The microbiome plays an essential role in developing the body's immune cells for the emerging competent vaccination process, ensuring herd immunity. Frequency of interaction among microbiota, metabolic nutrients and individual immunity preserve the degree of vaccine effectiveness against several pathogens. Microbiome symbiosis regulates pathogen transmissibility and the success of vaccination among different age groups. Imbalance of nutrients perturbs microbiota and abrogates immunity. Thus, a particular population can become vulnerable to the infection. Intestinal dysbiosis leads to environmental enteropathy (EE). As a consequence, the generation of herd immunity can either be delayed or not start in a particular cohort. Moreover, disparities of the protective response of many vaccines in developing countries outside of developed countries are due to inconsistencies of healthy microbiota among the individuals. We suggested that pan-India poliovirus vaccination program, capable of inducing herd immunity among communities for the last 30 years, may also influence the inception of natural course of heterologous immunity against SARS-CoV-2 infection. Nonetheless, this anamnestic recall is somewhat counterintuitive, as antibody generation against original antigens of SARS-CoV-2 will be subdued due to original antigenic sin.

A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge.

The envelope glycoprotein (Env) trimer ((gp120/gp41)3) mediates human immunodeficiency virus (HIV-1) entry into cells. The "closed," antibody-resistant Env trimer is driven to more open conformations by binding the host receptor, CD4. Broadly neutralizing antibodies that recognize conserved elements of the closed Env are potentially protective, but are elicited inefficiently. HIV-1 has evolved multiple mechanisms to evade readily elicited antibodies against more open Env conformations. Small-molecule CD4-mimetic compounds (CD4mc) bind the HIV-1 gp120 Env and promote conformational changes similar to those induced by CD4, exposing conserved Env elements to antibodies. Here, we show that a CD4mc synergizes with antibodies elicited by monomeric HIV-1 gp120 to protect monkeys from multiple high-dose intrarectal challenges with a heterologous simian-human immunodeficiency virus (SHIV). The protective immune response persists for at least six months after vaccination. CD4mc should increase the protective efficacy of any HIV-1 Env vaccine that elicits antibodies against CD4-induced conformations of Env.

Heterologous vaccine effects.

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.

The effects of vitamin A supplementation with measles vaccine on leucocyte counts and in vitro cytokine production.

As WHO recommends vitamin A supplementation (VAS) at vaccination contacts after age 6 months, many children receive VAS together with measles vaccine (MV). We aimed to investigate the immunological effect of VAS given with MV. Within a randomised placebo-controlled trial investigating the effect on overall mortality of providing VAS with vaccines in Guinea-Bissau, we conducted an immunological sub-study of VAS v. placebo with MV, analysing leucocyte counts, whole blood in vitro cytokine production, vitamin A status and concentration of C-reactive protein (CRP). VAS compared with placebo was associated with an increased frequency of CRP ≥ 5 mg/l (28 v. 12%; P=0·005). Six weeks after supplementation, VAS had significant sex-differential effects on leucocyte, lymphocyte, monocyte and basophil cell counts, decreasing them in males but increasing them in females. Mainly in females, the effect of VAS on cytokine responses differed by previous VAS: in previous VAS recipients, VAS increased the pro-inflammatory and T helper cell type 1 (Th1) cytokine responses, whereas VAS decreased these responses in previously unsupplemented children. In previous VAS recipients, VAS was associated with increased IFN-γ responses to phytohaemagglutinin in females (geometric mean ratio (GMR): 3·97; 95% CI 1·44, 10·90) but not in males (GMR 0·44; 95% CI 0·14, 1·42); the opposite was observed in previously unsupplemented children. Our results corroborate that VAS provided with MV has immunological effects, which may depend on sex and previous VAS. VAS may increase the number of leucocytes, but also repress both the innate and lymphocyte-derived cytokine responses in females, whereas this repression may be opposite if the females have previously received VAS.

The heterologous (non-specific) effects of vaccines: implications for policy in high-mortality countries.

There are important interactions between vaccines, and between vaccines and unrelated (heterologous) infections. In high-mortality regions, until the next vaccine is given, live vaccines such as bacillus Calmette-Guérin (BCG) and measles vaccines reduce mortality from infections such as pneumonia and sepsis. However, non-live vaccines such as diphtheria, tetanus and whole-cell pertussis vaccine (DTP) may increase mortality from infections other than diphtheria, tetanus and pertussis. All-cause mortality might be reduced if an extra dose of Edmonston-Zagreb measles vaccine were given at 20 weeks of age, 4-6 weeks after the third dose of DTP, with no subsequent doses of DTP in girls, and no vitamin A in girls or boys before the second dose of measles vaccine at 9 months of age. Policy should change to increase the proportion of babies given BCG and oral polio vaccine at birth, and should recognize the important differences between BCG, DTP and measles vaccines produced by different manufacturers.

Heterologous and sex differential effects of administering vitamin A supplementation with vaccines.

WHO recommends high-dose vitamin A supplementation (VAS) to children from 6 months to 5 years of age in low-income countries, in order to prevent and treat vitamin A deficiency-associated morbidity and mortality. The current policy does not discriminate this recommendation either by sex or vaccination status of the child. There is accumulating evidence that the effects of VAS on morbidity, mortality and immunological parameters depend on concomitant vaccination status. Moreover, these interactions may manifest differently in males and females. Certain vaccines administered through the Expanded Program on Immunization have been shown to alter all-cause mortality from infections other than the vaccine-targeted disease. This review summarizes the evidence from observational studies and randomized-controlled trials of the effects of VAS on these so-called heterologous or non-specific effects of vaccines, with a focus on sex differences. In general, VAS seems to enhance the heterologous effects of vaccines, particularly for diphtheria-tetanus-pertussis and live measles vaccines, where some studies, although not unanimously, show a stronger interaction between VAS and vaccination in females. We suggest that vaccination status and sex should be considered when evaluating the effects of VAS in early life.

The non-specific effects of vaccines and other childhood interventions: the contribution of INDEPTH Health and Demographic Surveillance Systems.

Most childhood interventions (vaccines, micronutrients) in low-income countries are justified by their assumed effect on child survival. However, usually the interventions have only been studied with respect to their disease/deficiency-specific effects and not for their overall effects on morbidity and mortality. In many situations, the population-based effects have been very different from the anticipated effects; for example, the measles-preventive high-titre measles vaccine was associated with 2-fold increased female mortality; BCG reduces neonatal mortality although children do not die of tuberculosis in the neonatal period; vitamin A may be associated with increased or reduced child mortality in different situations; effects of interventions may differ for boys and girls. The reasons for these and other contrasts between expectations and observations are likely to be that the immune system learns more than specific prevention from an intervention; such training may enhance or reduce susceptibility to unrelated infections. INDEPTH member centres have been in an ideal position to document such additional non-specific effects of interventions because they follow the total population long term. It is proposed that more INDEPTH member centres extend their routine data collection platform to better measure the use and effects of childhood interventions. In a longer perspective, INDEPTH may come to play a stronger role in defining health research issues of relevance to low-income countries.

[Features of patients with the multiple sensitization diagnostics before allergen specific immunotherapy will be set and the assessment of the therapy results with the laboratory methods].

BACKGROUND: Due to the wide expansion of atopy, its early beginning, variety of forms, difficulty of specific pathogenetic treatment, and also high cost of in vitro researches there is a need of diagnostic test systems development and optimization. AIM: To make the assessment of atopy diagnostics efficiency in children with a multiple allergy and the analysis of specific immunotherapy (ASIT) influence on immune markers level in serum for a choice of the most significant predictive indicator. PATIENTS AND METHODS: 457 children (mean age 8,9 ± 4,3 years) with pollinosis symptoms that prevalence in spring period were tested with birch pollen allergens extract by detecting allergen-specific immunoglobulin E (sIgE) levels. Than patient witch showed positive sIgE level (243 children) were tested with expanded set of plant allergens (birch, alder, hazel, oak pollen, allergens of Rosaceae family and carrot) and set of birch pollen allergocomponents (Bet v1, Bet v2, Bet v4, Bet v6). From them 32 patients were treated with allergen-specific immunotherapy. Immunological assays were performed by indirect immunofluorescent method on ImmunoCAP250 (Sweden). RESULTS: It was shown that birch allergens sIgE antibodies detection in patients with pollinosis allows to estimate sensitization degree to allergens of related trees and could predict their quantitative values. The oak allergens sIgE level is a good predictive marker of sIgE level to food plant derived allergens. And apple allergens sIgE concentration is closely assotiated with sIgE to fruit allergens of Rosacea family. Detection of sensitization to minor allergens in patient influences on therapy efficacy prognosis. CONCLUSION: sIgE detection to limited number of allergens (birch-oak-apple) is effective to sIgE value assessment in patient with allergy to plant causing allergens cross reactivity. Component-divided in vitro diagnostics directed on reveal of sensitization caused by minor allergens, is actual at the answer a question about ASIT validity and its efficiency. Component-divided in vitro diagnostics directed on reveal of sensitization caused by minor allergens, is actual at the answer a question about ASIT validity and its efficiency. Significant results of the therapy are shown after double course ASIT that also allows to reduce considerably production of sIgE antibodies to significant allergens, and cross reacting plant food allergens.