More than 9. An estimated 1. Thus the need for new, more effective TB vaccines is clear, and many groups are working toward this goal. This approach has been applied to HIV vaccines and resulted in encouraging results in one large-scale trial. See the tuberculosis entries in our collected disease timeline , and read about a global TB vaccination effort in the wake of World War Two in this blog post. Aeras Global TB Foundation.
Vaccine Science: TB Vaccine. World Health Organization. Meningococcal disease. Pneumococcal disease. Historical Medical Library. Calmette said that between and children had been vaccinated, of whom had mothers with TB, and the remainder had close contact with the disease.
Of these children only 3. This included criticism of the enormous rate of mortality from TB that was said by Calmette to normally apply to the children of those with TB, as well as children exposed to massive infection.
Despite this, at the Conference of the League of Nations in Paris in , the vaccine was recognized as safe and its use was encouraged. The history of the BCG vaccine nearly came to an end in when the Lubeck disaster occurred. This also cast doubts on the safety of BCG. Seventy two of the children developed TB and died within a year as a result of the disease.
A subsequent investigation carried out by German TB experts, revealed that the vaccine had become contaminated with the distinct virulent human strain during its preparation at a local laboratory. Although the BCG vaccine itself was eventually exonerated as the cause of the Lubeck disaster, its use declined for several years afterwards. The ancient innate immune system has evolved to employ multiple defense mechanisms to eliminate infection. In contrast to the adaptive immunity, which relies on the antigen-specificity, additional innate immune cell populations may exhibit heterologous memory responses triggered upon microbial exposure.
It is plausible that a cross-talk between macrophages and NK cells facilitates the fine-tuning of innate immune program during the life-time exposure to microbial insults. In support of this notion, vaccination of healthy volunteers with BCG primes macrophages and NK cells, leading to increased cytokine production after ex vivo restimulation 3 , Figure 1.
A BCG vaccination and Trained immunity. Trimethylation of the H3K4 histone predisposes the innate immune response to a secondary insult, leading to an increased production of pro-inflammatory cytokines. B Trained immunity as defense mechanism against respiratory infections.
BCG vaccination is given as an initial stimulus, leading to metabolic changes and epigenetic rewiring of innate immune cells, increasing the transcription of pro-inflammatory genes and secretion cytokines. BCG vaccinated individuals display an enhanced innate immune response following a secondary challenge, which may lead to protection against subsequent viral infections such as Influenza A virus or Respiratory syncytial virus RSV. A recent study from Netea et al.
To explain this, there is another type of immunological mechanism by which BCG could be inducing cross-protection named heterologous immunity. The term heterologous immunity refers to the immunity that can develop to one pathogen after an individual has been exposed to a non-identical pathogen.
Therefore, a combination of trained immunity and heterologous immunity by some BCG epitopes could provide immunity through T-cell cross-reactivity that could be responsible for the beneficial clinical effects of BCG.
In addition to trial design, the heterogeneity of BCG strains may also influence safety and effectiveness of vaccines against respiratory infections. It was suggested that the strain variation may contribute to the highly variable protective efficacy of BCG against TB observed in clinical trials.
The comparative genomic analysis studies and more recently conducted transcriptional and proteomics profiling experiments have produced a comprehensive map of single nucleotide polymorphisms SNPs , deletions, insertions, and duplications of genomic regions across 14 BCG strains 25 , The more virulent strains were also more effective in protection against Mycobacterium tuberculosis challenge At molecular level, BCG-Japan, -Moreau, and -Glaxo strains are naturally defective in the production of phthiocerol dimycocerosates PDIMs and phenolic glycolipids PGLs , two lipid virulence factors, which could compromise their effectiveness during vaccination Therefore, selection of the BCG strain, vaccine formulation and route of the administration may ultimately impact the effectiveness of these vaccines against COVID in clinical trials Figure 2.
B BCG strains in ongoing clinical trials. Initial ecological studies established that in countries with BCG vaccination programs have less COVID cases and deaths per population 31 , 32 , suggesting that trained immunity inducing vaccines may provide protection to bridge the gap before a COVIDspecific vaccine is developed It is possible that due to the different testing and notification approaches, case and deaths incidences of COVID might not differ in a country with BCG vaccination as it is critical to include different variables of interest such as age structure, income, rurality, and population density.
Similar conclusions were reached comparing the same geographical area with similar socioeconomic conditions between Spain and Portugal, with different high mortality rates have been observed in Spain where TB vaccination is no longer part of the official vaccination calendar In this trial in which elderly people participated, it was demonstrated the difference between the incidence of new infections after placebo vaccination Furthermore, vaccinated individuals took longer to get infected 16 weeks than the ones vaccinated with placebo 11 weeks.
Supporting this view, all BCG vaccinated patients showed an increased proinflammatory pattern after a second stimulation of peripheral blood mononuclear cells PBMCs with heat-killed C.
The study concluded that BCG vaccination is safe, as recently reported by the same group 17 , and can protect the elderly against infections. Such therapeutic vaccination strategy addresses the hypothesis that the induction of both innate and viral-specific immune responses might be beneficial during active SARS-CoV-2 antigenic exposure and provides further rationale for combining BCG-based vaccines with other approved vaccines.
Recent preclinical evidence corroborated this notion: BCG:CoVac, a formulation combining BCG with a stabilized form of the spike S protein resulted in the stimulation of SARS-CoVspecific antibody and T-cell responses in mice at the levels equivalent to or exceeding responses elicited by current clinical-stage vaccines in the murine models Unlike other vaccination platforms, the robust safety and immunogenicity profile of BCG has rendered it an attractive vector for vaccine development against many viral or bacterial diseases.
Furthermore, when administered in early life, BCG vaccination can act as an adjuvant enhancing antibody responses to recombinant hepatitis B surface antigen rHBsAg both in mice and in human infants 49 , One of the prominent novel approaches is the development of live rBCG engineered to express SARS-CoV-2 antigens to enhance innate and adaptive immune responses and induce sustained antigen presentation.
The overall design strategy is based on the hypothesized ability of rBCG-SARS-CoV-2 bacteria to deliver antigens to lymphoid organs, prime a polyfunctional T-cell response and induce long-term systemic and pulmonary protective T-cell immunity.
Overall, T-cell responses against the S, N, and M antigens have been reported to be the most dominant and long lasting Several groups around the world are currently pursuing the construction of such next-generation BCG-based vaccines 52 , VPM expresses listeriolysin O LLO derived from Listeria monocytogenes and deleted Urease C ureC gene and has been demonstrated to be safer and more immunogenic in preclinical studies A different approach by Carlos Martin and colleagues generated a live attenuated M.
This represents a unique approach that does not use a cow-derived attenuated M. The mechanisms by which BCG induces a cross-protection against other diseases and specifically respiratory tract infections, has been stablished during the last decade and suggests a critical role of the innate immune system The concept of trained immunity brings new insights into the immunological memory concept and described that cells from the innate immune system, such as macrophages, are able to recall a first encounter with a pathogen and produce an enhanced response toward a second assault.
As a result, several studies on the cross-protective effects of the BCG vaccines have demonstrated that the positive effects on susceptibility to viral respiratory infections is associated with induction of trained immunity. BCG vaccination should not be given to persons who are immunosuppressed e. BCG vaccination should not be given during pregnancy. Even though no harmful effects of BCG vaccination on the fetus have been observed, further studies are needed to prove its safety.
BCG vaccination may cause a false-positive reaction to the TST, which may complicate decisions about prescribing treatment. See below for specific guidance on skin test results. TB Blood Tests. Persons in the following high-risk groups should be given treatment for LTBI if their reaction to the TST is at least 5 mm of induration or they have a positive result using a TB blood test:.
In addition, persons in the following high-risk groups should be considered for treatment of LTBI if their reaction to the TST is at least 10 mm of induration or they have a positive result using a TB blood test:. Persons with no known risk factors for TB may be considered for treatment of LTBI if their reaction to the tuberculin test is at least 15 mm of induration or they have a positive result using a TB blood test.
Targeted skin testing programs should only be conducted among high-risk groups.
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