Revaccination with Bacille Calmette-Guérin (BCG) is associated with an increased risk of abscess and lymphadenopathy

The reported frequency and types of adverse events following initial vaccination and revaccination with Bacille Calmette-Guérin (BCG) varies worldwide. Using active surveillance in a randomised controlled trial of BCG vaccination (the BRACE trial), we determined the incidence and risk factors for the development of BCG injection site abscess and regional lymphadenopathy. Injection site abscess occurred in 3% of 1387 BCG-vaccinated participants; the majority (34/41, 83%) resolved without treatment. The rate was higher in BCG-revaccinated participants (OR 3.6, 95% CI 1.7–7.5), in whom abscess onset was also earlier (median 16 vs. 27 days, p = 0.008). No participant with an abscess had a positive interferon-gamma release assay. Regional lymphadenopathy occurred in 48/1387 (3%) of BCG-vaccinated participants, with a higher rate in revaccinated participants (OR 2.1, 95% CI 1.1–3.9). BCG-associated lymphadenopathy, but not injection site abscess, was influenced by age and sex. A previous positive tuberculin skin test was not associated with local reactions. The increased risk of injection site abscess or lymphadenopathy following BCG revaccination is relevant to BCG vaccination policy in an era when BCG is increasingly being considered for novel applications.

After 100 Years of BCG Immunization against Tuberculosis, What Is New and Still Outstanding for This Vaccine?

In 2021, most of the world was reasonably still concerned about the COVID-19 pandemic, how cases were up and down in different countries, how the vaccination campaigns were ongoing, and most people were familiar with the speed with which vaccines against SARS-Co-V2 were developed, analyzed, and started to be applied in an attempt to curb the pandemic. Because of this, it may have somehow passed relatively inadvertently for people outside of the field that the vaccine used to control tuberculosis (TB), Mycobacterium bovis Bacille Calmette-Guérin (BCG), was first applied to humans a century ago. Over these years, BCG has been the vaccine applied to most human beings in the world, despite its known lack of efficacy to fully prevent respiratory TB. Several strategies have been employed in the last 20 years to produce a novel vaccine that would replace, or boost, immunity and protection elicited by BCG. In this work, to avoid potential redundancies with recently published reviews, I only aim to present my current thoughts about some of the latest findings and outstanding questions that I consider worth investigating to help develop a replacement or modified BCG in order to successfully fight TB, based on BCG itself.

A Short History of the BCG Vaccine

BCG vaccine continues to be controversial, live attenuated BCG is still the only vaccine in use which is able to prevent TB in humans. It is still difficult to determine which strain should be used and further detailed analysis of the genomics and immunogenicity of BCG sub-strains may provide an answer to this important question. The only vaccine available is the BCG (Bacille Calmette-Guerin), that has been used for about 100 years, with remarkable results. The majority of the world followed the lead of Europe and the WHO and introduced routine BCG vaccination according to various schedules. According to the Methodological Guide for the Implementation of the National Program for the Prevention, Surveillance and Control of Tuberculosis, BCG vaccination is indicated for all newborns, at the age of 2-7 days (if there are no contraindications), before discharge from maternity and without preliminary tuberculin test.

Bacille Calmette-Guérin vaccine reprograms human neonatal lipid metabolism in vitro and in vivo

SummaryVaccines have generally been developed with limited insight into their molecular impact. While systems vaccinology, including metabolomics, enables new characterization of vaccine mechanisms of action, these tools have yet to be applied to infants at high risk of infection and receive the most vaccines. Bacille Calmette-Guérin (BCG) protects infants against disseminated tuberculosis (TB) and TB-unrelated infections via incompletely understood mechanisms. We employed mass spectrometry-based metabolomics of blood plasma to profile BCG-induced infant responses in Guinea Bissau in vivo and the U.S. in vitro. BCG selectively altered plasma lipid pathways, including lysophospholipids. BCG-induced lysophosphatidylcholines (LPCs) correlated with both TLR agonist- and purified protein derivative (PPD, mycobacterial antigen)-induced blood cytokine production in vitro, raising the possibility that LPCs contribute to BCG immunogenicity. Analysis of an independent newborn cohort from The Gambia demonstrated shared vaccine-induced metabolites such as phospholipids and sphingolipids. BCG-induced changes to the plasma lipidome and LPCs may contribute to its immunogenicity and inform the discovery and development of early life vaccines.HighlightsNeonatal BCG immunization generates distinct metabolic shifts in vivo and in vitro across multiple independent cohorts.BCG induces prominent changes in concentrations of plasma lysophospholipids (LPLs)BCG induced changes in plasma lysophosphatidylcholines (LPCs) correlate with BCG effects on TLR agonist- and mycobacterial antigen-induced cytokine responses.Characterization of vaccine-induced changes in metabolism may define predictive signatures of vaccine responses and inform early life vaccine development.Abstract FigureGraphical abstract:BCG vaccination perturbs metabolic pathways in vivo and in vitro.Vaccines have traditionally been developed empirically, with limited insight into their impact on molecular pathways. Metabolomics provides a new approach to characterizing vaccine mechanisms but has not yet been applied to human newborns, who are at the highest risk of infection and receive the most vaccines. Bacille Calmette-Guérin (BCG) prevents disseminated mycobacterial disease in children and can induce broad protection to reduce mortality due to non-TB infections. Underlying mechanisms are incompletely characterized. Employing mass spectrometry-based metabolomics, we demonstrate that early BCG administration alters the human neonatal plasma metabolome, especially lipid metabolic pathways such as lysophosphatidylcholines (LPCs), both in vivo and in vitro. Plasma LPCs correlated with both innate TLR-mediated and PPD antigen-induced cytokine responses suggesting that BCG-induced lipids might contribute to the immunogenicity of this vaccine. Vaccine-induced metabolic changes may provide fresh insights into vaccine immunogenicity and inform the discovery and development of early life vaccines.

Reactivation of BCG vaccination scars after vaccination with mRNA-Covid-vaccines: two case reports

Background From May 2020 to January 2021, we enrolled 1233 health care workers (HCW) from Danish Hospitals in a randomized trial evaluating whether Bacille Calmette-Guérin (BCG) provides protection against COVID-19. Participants were randomized 1:1 to BCG vs saline and followed for 6 months. From December 2020, Covid-19 vaccines were offered to the HCW. In most cases, BCG vaccination results in a characteristic scar. Reactivation of the BCG scar has been described in children during viral infections and following influenza vaccination, but is mostly associated to Kawasaki’s disease, a disease entity with pathogenesis likely similar to the child Covid-19 complication MIS-C: Multi-System Inflammatory Syndrome. Reactivation of scars after neonatal BCG vaccination has recently been described in four women after Covid-19 mRNA vaccination. Two of our trial participants experienced reactivation of their novel BCG scars after receiving mRNA Covid-19 vaccination 6 to 8 months post-BCG. Case presentations Two female HCW participants that had been randomly allocated to BCG in the BCG-DENMARK-COVID trial, spontaneously reported itching and secretion at the BCG scar site after having received mRNA Covid-19 vaccination (Moderna and Pfizer-BioNTech) 6 to 8 months following inclusion and BCG vaccination. One participant, who had a larger BCG skin reaction, noticed re-appearing symptoms after both the first and the second COVID-vaccine dose, while the other participant only noted symptoms after the second dose. Both had been BCG vaccinated during childhood, and no reactivation was noted in the older scars. No treatment was needed or provided. Conclusions The reactivation of the BCG scar after receiving mRNA vaccine might have been caused by cross-reactivity between BCG and SARS-CoV-2. In both cases, the symptoms were bothersome, but self-limiting and left no sequelae. The risk of reactivation at the scar site is thus not a reason to avoid vaccination with either vaccine.

Efficacy and immunogenicity of different BCG doses in BALB/c and CB6F1 mice when challenged with H37Rv or Beijing HN878

Two strains of mice (BALB/c and CB6F1) were vaccinated with a range of Bacille Calmette-Guérin (BCG) Danish doses from 3 × 105 to 30 CFU/mouse, followed by aerosol infection with Mtb (H37Rv or West-Beijing HN878 strain). The results indicated that both strains of mice when infected with HN878 exhibited significant protection in their lungs with BCG doses at 3 × 105—3000 CFU (BALB/c) and 3 × 105—300 CFU (CB6F1). Whereas, a significant protection was seen in both strains of mice with BCG doses at 3 × 105—300 CFU when infected with H37Rv. A significant increase in the frequencies of BCG-specific IFNγ+ IL2+ TNFα+ CD4 T cells in the BCG doses at 3 × 105—3000 CFU (BALB/c) and 3 × 105—300 CFU (CB6F1) was seen. The IFNγ+ IL2+ TNFα+ CD4 T cells correlated with the Mtb burden in the lungs of HN878 infected mice (BALB/c and CB6F1) whereas, IFNγ+ TNFα+ CD4 T cells correlated with the BALB/c mice infected with H37Rv or HN878. The BCG dose at 3000 CFU (an equivalent single human dose in the mice by body weight) is protective in both strains of mice infected with H37Rv or HN878 and may serve an interesting dose to test new TB vaccine in a preclinical animal model.

A COVID-19 NAS GESTANTES: UMA REVISÃO DE LITERATURA

O artigo busca elucidar dúvidas tais quais: amamentação, via de parto, condutas obstétricas frequentes em gestantes com suspeita ou confirmação de Covid-19. Do mesmo modo servir como guia para médicos, trazendo informações atualizadas da literatura e divulgadas pelas principais instituições internacionais de obstetrícia. Foi realizada uma revisão em 43 artigos, publicados pelas 11 maiores instituições de obstetrícia, as quais relatam as principais recomendações referentes à infecção por coronavírus na gestação. Discute-se a possibilidade de transmissão vertical, teratogenicidade, quadro clínico esperado e seu agravamento, métodos diagnósticos e recomendações em relação à profilaxia medicamentosa e comportamental. Sabe-se que grávidas negras, asiáticas, com mais de 35 anos, no terceiro trimestre de gestação, com comorbidades respiratórias, hipertensão, diabetes ou soropositivas possuem maior risco de adoecimento e internação. Sem registros de transmissão vertical, porém, a infecção materna aumenta o risco de complicações fetais, tais como febre, tosse, mialgia, dispneia, odinofagia, anosmia, náuseas e vômitos, congestão nasal e ageusia. O agravamento da doença é caracterizado por hipotensão, taquipneia, alteração do nível de consciência, redução do débito urinário e saturação de oxigênio menor que 93%. No diagnóstico, o teste de antígenos e o RT-PCR são os mais utilizados. As medidas profiláticas com hidroxicloroquina ou vacinação com Bacille-Calmette-Guerin (BCG) não apresentam eficácia comprovada cientificamente, sendo, portanto, recomendadas somente medidas preventivas relacionadas ao contato com o novo vírus. Por ser um vírus novo, ainda há algumas contradições e contraindicações referentes ao manejo clínico, desse modo, o presente artigo busca disseminar informações valiosas para o tratamento eficaz das pacientes acometidas.

A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilising immunity against SARS-CoV-2 infection

Global control of COVID-19 requires broadly accessible vaccines that are effective against SARS-CoV-2 variants. In this report, we exploit the immunostimulatory properties of bacille Calmette-Guérin (BCG), the existing tuberculosis vaccine, to deliver a vaccination regimen with potent SARS-CoV-2-specific protective immunity. Combination of BCG with a stabilised, trimeric form of SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the blood of vaccinated mice, that was further augmented by the addition of alum. This vaccine formulation, BCG:CoVac, induced high-titre SARS-CoV-2 neutralising antibodies (NAbs) and Th1-biased cytokine release by vaccine-specific T cells, which correlated with the early emergence of T follicular helper cells in local lymph nodes and heightened levels of antigen-specific plasma B cells after vaccination. Vaccination of K18-hACE2 mice with a single dose of BCG:CoVac almost completely abrogated disease after SARS-CoV-2 challenge, with minimal inflammation and no detectable virus in the lungs of infected animals. Boosting BCG:CoVac-primed mice with a heterologous vaccine further increased SARS-CoV-2-specific antibody responses, which effectively neutralised B.1.1.7 and B.1.351 SARS-CoV-2 variants of concern. These findings demonstrate the potential for BCG-based vaccination to protect against major SARS-CoV-2 variants circulating globally.