Bacille Calmette-Guérin: An ophthalmic perspective.

Vaccines such as bacille Calmette-Guérin (BCG) are known for their heterologous effects mediated through a number of mechanisms, including trained immunity constituted by monocyte-macrophage based innate immunity. Other events such as direct hematogenous spread and induction of autoimmunity are also described. There has been a resurgent interest in harnessing some of the benefits of trained immunity in the management of COVID-19, even as several specific vaccines have been approved. We summarize the current knowledge of ocular effects of BCG. Potential effect of granulomatous inflammation on angiotensin converting enzyme activity and accentuation of cytokine storm that may result in undesirable ocular and systemic effects are also discussed.

Sequence similarity of HSP65 of Mycobacterium bovis BCG with SARS-CoV-2 spike and nuclear proteins: may it predict an antigen-dependent immune protection of BCG against COVID-19?

The Bacillus Calmette-Guérin (BCG) vaccine is known to have protective effects not only against tuberculosis but also against other unrelated infectious diseases caused by different pathogens. Several epidemiological studies have also documented the beneficial influence of BCG vaccine in reducing both susceptibility to and severity of SARS-CoV-2 infection. The protective, non-specific effects of BCG vaccination would be related to an antigen-independent enhancement of the innate immunity, termed trained immunity. However, the knowledge that heat shock protein (HSP)65 is the main antigen of Mycobacterium bovis BCG prompted us to verify whether sequence similarity existed between HSP65 and SARS-CoV-2 spike (S) and nuclear (N) proteins that could support an antigen-driven immune protection of BCG vaccine. The results of the in silico investigation showed an extensive sequence similarity of HSP65 with both the viral proteins, especially SARS-CoV-2 S, that also involved the regions comprising immunodominant epitopes. The finding that the predicted B cell and CD4+ T cell epitopes of HSP65 shared strong similarity with the predicted B and T cell epitopes of both SARS-CoV-2 S and N would support the possibility of a cross-immune reaction of HSP65 of BCG with SARS-CoV-2.

Cheap and Commonplace: Making the Case for BCG and γδ T Cells in COVID-19.

Antigen-specific vaccines developed for the COVID-19 pandemic demonstrate a remarkable achievement and are currently being used in high income countries with much success. However, new SARS-CoV-2 variants are threatening this success via mutations that lessen the efficacy of antigen-specific antibodies. One simple approach to assisting with this issue is focusing on strategies that build on the non-specific protection afforded by the innate immune response. The BCG vaccine has been shown to provide broad protection beyond tuberculosis disease, including against respiratory viruses, and ongoing studies are investigating its efficacy as a tool against SARS-CoV-2. Gamma delta (γδ) T cells, particularly the Vδ2 subtype, undergo rapid expansion after BCG vaccination due to MHC-independent mechanisms. Consequently, γδ T cells can produce diverse defenses against virally infected cells, including direct cytotoxicity, death receptor ligands, and pro-inflammatory cytokines. They can also assist in stimulating the adaptive immune system. BCG is affordable, commonplace and non-specific, and therefore could be a useful tool to initiate innate protection against new SARS-CoV-2 variants. However, considerations must also be made to BCG vaccine supply and the prioritization of countries where it is most needed to combat tuberculosis first and foremost.

Synthetic protein conjugate vaccines provide protection against Mycobacterium tuberculosis in mice.

The global incidence of tuberculosis remains unacceptably high, with new preventative strategies needed to reduce the burden of disease. We describe here a method for the generation of synthetic self-adjuvanted protein vaccines and demonstrate application in vaccination against Mycobacterium tuberculosis Two vaccine constructs were designed, consisting of full-length ESAT6 protein fused to the TLR2-targeting adjuvants Pam2Cys-SK4 or Pam3Cys-SK4 These were produced by chemical synthesis using a peptide ligation strategy. The synthetic self-adjuvanting vaccines generated powerful local CD4+ T cell responses against ESAT6 and provided significant protection in the lungs from virulent M. tuberculosis aerosol challenge when administered to the pulmonary mucosa of mice. The flexible synthetic platform we describe, which allows incorporation of adjuvants to multiantigenic vaccines, represents a general approach that can be applied to rapidly assess vaccination strategies in preclinical models for a range of diseases, including against novel pandemic pathogens such as SARS-CoV-2.

BCG vaccination history associates with decreased SARS-CoV-2 seroprevalence across a diverse cohort of health care workers.

BACKGROUNDSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 1 million deaths worldwide; thus, there is an urgent need to develop preventive and therapeutic strategies. The antituberculosis vaccine bacillus Calmette-Guérin (BCG) demonstrates nonspecific, protective innate immune-boosting effects. Here, we determined whether a history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a longitudinal, retrospective observational study of a diverse cohort of health care workers (HCWs).METHODSWe assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, which included information on BCG vaccination status and preexisting demographic and clinical characteristics, from an observational cohort of HCWs in a multisite Los Angeles health care organization. We used multivariate analysis to determine whether a history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion.RESULTSOf the 6201 HCWs, 29.6% reported a history of BCG vaccination, whereas 68.9% had not received BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as the incidence of self-reported clinical symptoms associated with coronavirus disease 2019 (COVID-19) were markedly decreased among HCWs with a history of BCG vaccination compared with those without BCG vaccination. After adjusting for age and sex, we found that a history of BCG vaccination, but not meningococcal, pneumococcal, or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion.CONCLUSIONSA history of BCG vaccination was associated with a decrease in the seroprevalence of anti-SARS-CoV-2 IgG and a lower number of participants who self-reported experiencing COVID-19-related clinical symptoms in this cohort of HCWs. Therefore, large randomized, prospective clinical trials of BCG vaccination are urgently needed to confirm whether BCG vaccination can confer a protective effect against SARS-CoV-2 infection.

Bacillus Calmette-Guerin Vaccine and Nonspecific Immunity.

Bacillus Calmette-Guerin (BCG) vaccine is one of the most widely used vaccines in the world. It protects against many non-mycobacterial infections secondary to its nonspecific immune effects. The mechanism for these effects includes modification of innate and adaptive immunity. The alteration in innate immunity is through histone modifications and epigenetic reprogramming of monocytes to develop an inflammatory phenotype, a process called "trained immunity." The memory T cells of adaptive immunity are also responsible for resistance against secondary infections after administration of BCG vaccine, a process called "heterologous immunity." Bacillus Calmette-Guerin vaccine is known to not only boosts immune responses to many vaccines when they are co-administered but also decrease severity of these infections when used alone. The BCG vaccine by itself induces a TH1 type response, and its use as a vector has also shown promising results. This review article summarizes the studies showing effects of BCG vaccines on various viral infections, its role in enhancing vaccine responses, the mechanisms for this protective effect, and information on its effect on COVID-19.

Footprint of the COVID-19 Pandemic in India: A Study of Immune Landscape and Other Factors Shielding Mortality.

The impact of the SARS-CoV-2 pandemic has significantly affected global health and created a world crisis. The exponentially increasing numbers of infection and mortality have made preventive measures challenging. India being a highly populated nation has so far effectively counteracted the pandemic outbreak with a significantly lower rate of mortality despite the high infection rates. The genetic architecture of the immune response genes in the Indian population, BCG vaccination, the predominantly young age group of people, and their traditional food habits might contribute to the lower rate of mortality. Human leukocyte antigens (HLA) play a vital role in triggering T cells, and natural killer (NK) cells can immediately react to eliminate infected cells. Activation of virus-specific CD4+ T cells and CD8+ cytotoxic T cells selectively targets the infected cells and strengthens the immunoregulatory system. The checkpoint for NK cell function is the engagement of killer Ig-like receptors (KIR) molecules with their respective HLA ligands overexpressed or expressed on the compromised virus-infected cells which have shown polymorphism among different ethnic groups. Here, we explore if certain KIR-HLA motifs grant Indians a survival advantage in terms of the low rate of mortality. Additionally, enhanced immunity through BCG vaccination may favor fruitful eradication of SARS-CoV-2 and provide the way out as in therapeutic intervention and vaccination strategies.

Bacillus Calmette-Guérin (BCG) vaccine generates immunoregulatory cells in the cervical lymph nodes in guinea pigs injected intra dermally.

This work demonstrates the presence of immune regulatory cells in the cervical lymph nodes draining Bacillus Calmette-Guérin (BCG) vaccinated site on the dorsum of the ear in guinea pigs. It is shown that whole cervical lymph node cells did not proliferate in vitro in the presence of soluble mycobacterial antigens (PPD or leprosin) despite being responsive to whole mycobacteria. Besides, T cells from these lymph nodes separated as a non-adherent fraction on a nylon wool column, proliferated to PPD in the presence of autologous antigen presenting cells. Interestingly, addition of as low as 20% nylon wool adherent cells to these, sharply decreased the proliferation by 83%. Looking into what cells in the adherent fraction suppressed the proliferation, it was found that neither the T cell nor the macrophage enriched cell fractions of this population individually showed suppressive effect, indicating that their co-presence was necessary for the suppression. Since BCG induced granulomas resolve much faster than granulomas induced by other mycobacteria such as Mycobacterium leprae the present experimental findings add to the existing evidence that intradermal BCG vaccination influences subsequent immune responses in the host and may further stress upon its beneficial role seen in Covid-19 patients.

BCG vaccine: a hope to control COVID-19 pandemic amid crisis.

COVID-19 caused by the virus SARS-CoV-2 has gripped essentially all countries in the world, and has infected millions and killed hundreds of thousands of people. Several innovative approaches are in development to restrain the spread of SARS-CoV-2. In particular, BCG, a vaccine against tuberculosis (TB), is being considered as an alternative therapeutic modality. BCG vaccine is known to induce both humoral and adaptive immunities, thereby activating both nonspecific and cross-reactive immune responses in the host, which combined could effectively resist other pathogens including SARS-CoV-2. Notably, some studies have revealed that SARS-CoV-2 infectivity, case positivity, and mortality rate have been higher in countries that have not adopted BCG vaccination than in countries that have done so. This review presents an overview of the concepts underlying BCG vaccination and its nonspecific immuological effects and protection, resulting in 'trained immunity' and potential utility for resisting COVID-19.