Figure 1. Trinity of the immune system development and vaccine efficiency. The immune system and microbiota mutually co-evolve together in a symbiotic relationship. The impact of microbiome on the immune system development cannot be ignored. From fetus to adulthood, microbiomes are synchronized by maternal transfer and environmental factors. Early maternal factors such as mode of delivery, breastfeeding, antibiotics and diets all influence the immune system. Hence, all have an impact on subsequent immunological responses to many vaccines. Development of herd immunity in a community against any infection is the result of a complex outcome of host-specific factors such as microbiota, metabolism and environmental conditions. Malnutrition and repeated gastrointestinal infections reduce many vaccines’ efficacy. Microbial dysbiosis, along with environmental enteropathy (EE) influences undernourishment. It impairs the immune system development and decreases the efficiency of vaccines in a community, thereby compromising herd immunity.

Figure 2. Vaccine efficiency depends on the repertoire diversity of T-cells and B-cells. (a) Upon contact with antigen-presenting cells (APCs) through the T-cell receptor (TCR)–antigen–major histocompatibility complex (MHC) complex, naïve T-cells are differentiated into effector and memory T-cells. Based on the antigenic property, effector T-cells are of two types, i.e., CD4+ T-helper (Th) or CD8+ T-cytotoxic (Tc) cells. Antigens exposed by MHCII binds with TCRs of Th cells and antigens exposed by MHCI binds with TCRs of Tc cells. Th cells have the potential to further differentiate into Th1, Th2, Th17 and induced regulatory T-cells (iTreg), a process controlled by the lineage-specific transcription factors and effector cytokines produced by APCs. Effectiveness of memory T-cells decides the efficacy of vaccination; (b) B-cells (APCs) recognize antigens by their B-cell receptors (BCRs), followed by internalization of antigens and presented to Th cells, which are specific to same antigen. The TCRs of Th cells interact with antigens exposed by MHCII of B-cells. Then, activated B-cells trigger their own proliferation and differentiate into antibody-secreting plasma cells and memory B-cells. Activation and class switching of B-cells is the key factor for the success of immunization.

Figure 3. Herd immunity and microbiota. Maturity of the herd immunity against any infectious disease is a significant means of acquiring protection during an epidemic or pandemic situations. A spatial community is occupied by people having a variable degree of resistance against a particular infection. Microbial symbiosis regulates pathogen transmission dynamics and the efficacy of vaccination among different individuals in a population, promoting the development of herd immunity. In contrast, dysbiosis of the microbiome causes immune dysregulation, generating the suboptimal immune response and negative impacts on a vaccination program. Therefore, the number of sick individuals increases in a particular cohort. This reduces the chances of evolving herd immunity and increases the sick and contagious patients in a community.

Figure 4. Initial immune response to any pathogen involves the activation of innate immunity. Innate immunity is activated by germline encoded PRRs which recognize PAMPs and DAMPs of the microbes. Specific PRRs mainly include membrane-bound several TLRs, cytosolic DNA sensor, e.g., STING, Rig -1 like receptor (RLR), MDA5, NOD-like receptor, all of which coordinate with the host innate immune responses through the activation of the nuclear factor κB (NF-κB), activator protein 1 (AP-1) and interferon regulatory factor (IRF)-signaling pathway which triggers the antiviral interferons type I (IFNI) pathway. Activated innate immunity can commence the adaptive immunity by triggering both the T-cells and B-cells.

Figure 5. Yin and Yang of the heterologous immunity. (a) Heterologous immunity develops from the opinion where the antibody of one pathogen may protect an individual from a similar or in some cases even from phylogenetically distinct invaders. Vigorous immunization program with several vaccine candidates is required to improve protective response against any new incoming pathogen having comparable antigens. Both humoral and cellular cross-reactive heterologous memory responses may influence the foundation of the natural course of herd immunity against any new infection; (b) original antigenic sin refers to a phenomenon where the development of immunity against pathogens or antigens is shaped by the first exposure of related pathogens. The memory antibodies generated as a result of first exposure will interact with similar antigens of second pathogen for neutralizing it. This anamnestic recall against the second pathogen dampens the probability of immune system activation against original antigens of the second pathogen. This phenomenon is reasonably applicable to SARS-CoV-2 infection where its infection rate is very mild.

This entry is adapted from the peer-reviewed paper 10.3390/v12101150