BCG vaccine improves both Humoral and Cellular immune response against viruses and malignancies
March 23rd 2020
Researchers in four countries will soon start a clinical trial of an unorthodox approach to the new coronavirus. They will test whether a century-old vaccine against tuberculosis (TB), a bacterial disease, can strengthen the human immune system in a broad way, allowing it to better fight the virus that causes coronavirus disease 2019 and, perhaps, prevent infection with it altogether. The studies will be done in physicians and nurses, who are at higher risk of becoming infected with the respiratory disease than the general population, and in the elderly, who are at higher risk of serious illness if they become infected.
A team in the Netherlands will kick off the first of the trials this week. They will recruit 1,000 health care workers in eight Dutch hospitals who will either receive the vaccine, called bacillus Calmette-Guérin (BCG), or a placebo.
BCG contains a live, weakened strain of Mycobacterium bovis, a cousin of M. tuberculosis; the microbe that causes TB. (The vaccine is named after French microbiologists Albert Calmette and Camille Guérin, who developed it in the early 20th century.) The vaccine is given to children in their first year of life in most countries of the world, and is safe and cheap—but far from perfect: It prevents about 60% of TB cases in children on average, with large differences between countries.
Vaccines generally raise immune responses specific to a targeted pathogen, such as antibodies that bind and neutralize one type of virus but not others. But BCG may also increase the ability of the immune system to fight off pathogens other than the TB bacterium, according to clinical and observational studies published over several decades by Danish researchers Peter Aaby and Christine Stabell Benn, who live and work in Guinea-Bissau. They concluded the vaccine prevents about 30% to 40% of infections with any known pathogen, including viruses, in the first year after it’s given. The studies published in this field have been criticized for their methodology, however; a 2014 review ordered by the World Health Organization (WHO) concluded that BCG appeared to lower overall mortality in children, but rated confidence in the findings as “very low.” A 2016 review was a bit more positive about BCG’s potential benefits but said randomized trials were needed.
Since then, the clinical evidence has strengthened and several groups have made important steps investigating how BCG may generally boost the immune system in infections and in cancer. Mihai Netea, an infectious disease specialist at Radboud University Medical Center, discovered that the vaccine may defy textbook knowledge of how immunity works.
When a pathogen enters the body, white blood cells of the “innate” arm of the immune system attack it first; they may handle up to 99% of infections. If these cells fail, they call in the “adaptive” immune system, and T cells and antibody-producing B cells start to divide to join the fight. Key to this is that certain T cells or antibodies are specific to the pathogen; their presence is amplified the most. Once the pathogen is eliminated, a small portion of these pathogen-specific cells transform into memory cells that speed up T cell and B cell production the next time the same pathogen attacks. Vaccines are based on this mechanism of immunity.
The innate immune system, composed of white blood cells such as macrophages, natural killer cells, and neutrophils, was supposed to have no such memory. But Netea’s team discovered that BCG, which can remain alive in the human skin for up to several months, triggers not only Mycobacterium-specific memory B and T cells, but also stimulates the innate blood cells for a prolonged period. “Trained immunity,” Netea and colleagues call it. In a randomized placebo-controlled study published in 2018, the team showed that BCG vaccination protects against experimental infection with a weakened form of the yellow fever virus, which is used as a vaccine.
Together with Evangelos Giamarellos from the University of Athens, Netea has set up a study in Greece to see whether BCG can increase resistance to infections overall in elderly people. He is planning to start a similar study in the Netherlands soon. The trial was designed before the new coronavirus emerged, but the pandemic may reveal BCG’s broad effects more clearly, Netea says.
For the health care worker study, Neeta teamed up with epidemiologist and microbiologist Marc Bonten of UMC Utrecht. “There is a lot of enthusiasm to participate,” among the workers, Bonten says. The team decided not to use actual infection with coronavirus as the study outcome, but “unplanned absenteeism.” “We don’t have a large budget and it won’t be feasible to visit the sick professionals at home,” Bonten says. Looking at absenteeism has the advantage that any beneficial effects of the BCG vaccine on influenza and other infections may be captured as well, he says.
Although the study is randomized, participants will likely know if they got the vaccine instead of a placebo. BCG often causes a pustule at the injection site that may persist for months, usually resulting in a scar. But the researchers will be blinded to which arm of the study—vaccine or placebo—a person is in.
A research group at the University of Melbourne is setting up a BCG study among health care workers using the exact same protocol. Another research group at the University of Exeter will do a similar study in the elderly. And a team at the Max Planck Institute for Infection Biology last week announced that—inspired by Netea’s work—it will embark on a similar trial in elderly people and health workers with VPM1002, a genetically modified version of BCG that has not yet been approved for use against TB.
Eleanor Fish, an immunologist at the University of Toronto, says the vaccine probably won’t eliminate infections with the new coronavirus completely, but is likely to dampen significantly its impact on individuals. Fish says she’d take the vaccine herself if she could get a hold of it, and even wonders whether it’s ethical to withhold its potential benefits from trial subjects in the placebo arm.
But Netea says the randomized design is critical: “Otherwise we would never know if this is good for people.” The team may have answers within a few months.
BCG Vaccine for Health Care Workers as Defense against COVI- 19
SARS-CoV-2 spreads rapidly throughout the world. A large epidemic would seriously challenge the available hospital capacity, and this would be augmented by infection of healthcare workers (HCW). Strategies to prevent infection and disease severity of HCW are, therefore, desperately needed to safeguard continuous patient care. Bacille Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in in vitro and in vivo studies, and reported morbidity and mortality reductions as high as 70%. Furthermore, in our preliminary analysis, areas with existing BCG vaccination programs appear to have lower incidence and mortality from COVID191. The investigators hypothesize that BCG vaccination can reduce HCW infection and disease severity during the epidemic phase of SARS-CoV-2.
Location: M D Anderson Cancer Center, Houston, Texas
Mycobacterium bovis BCG in metastatic melanoma therapy
This review summarizes the used of wild-type and various rBCG strains as therapeutic agents for malignant melanoma (MM) to induce immunomodulatory activities and enhance antitumor immune responses, as well as its combination with chemotherapy and immunotherapy agents. Few rBCG constructs have been explored and little is known about the immunological basis and mechanisms of action leading to BCG-induced melanoma cell killing. Further investigation of these mechanisms of action will allow for the development of improved treatment strategies to improve the survival of MM patients.
Martha Lucia Ruiz Benitez, Camila Bonnemann Bender, Thaís Larré Oliveira, Kyle M. Schachtschneider, Tiago Collares & Fabiana Kömmling Seixas in: Applied Microbiology and Biotechnology volume 103, pages7903–7916(2019)
BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design
The Bacillus Calmette-Guérin (BCG) is a live attenuated tuberculosis vaccine that has the ability to induce non-specific cross-protection against pathogens that might be unrelated to the target disease. Vaccination with BCG reduces mortality in newborns and induces an improved innate immune response against microorganisms other than Mycobacterium tuberculosis, such as Candida albicans and Staphylococcus aureus. Innate immune cells, including monocytes and natural killer (NK) cells, contribute to this non-specific immune protection in a way that is independent of memory T or B cells. This phenomenon associated with a memory-like response in innate immune cells is known as “trained immunity.” Epigenetic reprogramming through histone modification in the regulatory elements of particular genes has been reported as one of the mechanisms associated with the induction of trained immunity in both, humans and mice. Indeed, it has been shown that BCG vaccination induces changes in the methylation pattern of histones associated with specific genes in circulating monocytes leading to a “trained” state. Importantly, these modifications can lead to the expression and/or repression of genes that are related to increased protection against secondary infections after vaccination, with improved pathogen recognition and faster inflammatory responses. In this review, we discuss BCG-induced cross-protection and acquisition of trained immunity and potential heterologous effects of recombinant BCG vaccines.
(Camila Covián, Ayleen Fernández-Fierro, Angello Retamal-Díaz, Fabián E. Díaz, Abel E. Vasquez, Margarita K. Lay, Claudia A. Riedel, Pablo A. González, Susan M. Bueno, and Alexis M. Kalergis in Front Immunol. 2019; 10: 2806)
Association of BCG Vaccination in Childhood with Subsequent Cancer Diagnoses
A 60-Year Follow-up of a Clinical Trial
What is the association of BCG vaccination during childhood with subsequent cancer development?
In this 60-year follow-up of a clinical trial of the BCG vaccine that included 2963 participants vaccinated at a median age of 8 years, those who received the BCG vaccine had a subsequent lung cancer rate of 18.2 cases per 100 000 person-years. Participants who received the placebo had a lung cancer rate of 45.4 cases per 100 000 person-years.
Meaning The findings suggest that receiving BCG vaccination during early childhood is associated with reduced risk of subsequent lung cancer development.
The BCG vaccine is currently the only approved tuberculosis vaccine and is widely administered worldwide, usually during infancy but also later in life. Previous studies found decreased rates of lymphoma and leukemia in BCG-vaccinated populations.
To determine whether BCG vaccination was associated with cancer rates in a secondary analysis of a BCG vaccine trial.
Design, Setting, and Participants Retrospective review (60-year follow-up) of a clinical trial in which participants were assigned to the vaccine group by systematic stratification by school district, age, and sex, then randomized by alternation. The original study was conducted at 9 sites in 5 US states between December 1935 and December 1998. Participants were 2963 American Indian and Alaska Native schoolchildren younger than 20 years with no evidence of previous tuberculosis infection. Statistical analysis was conducted between August 2018 and July 2019.
Single intradermal injection of either BCG vaccine or saline placebo.
Main Outcomes and Measures
The primary outcome was diagnosis of cancer after BCG vaccination. Data on participant interval health and risk factors, including smoking, tuberculosis infection, isoniazid use, and other basic demographic information, were also collected.
A total of 2,963 participants, including 1,540 in the BCG vaccine group and 1,423 in the placebo group, remained after exclusions. Vaccination occurred at a median (interquartile range) age of 8 (5-11) years; 805 participants (52%) in the BCG group and 710 (50%) in the placebo group were female. At the time of follow-up, 97 participants (7%) in the placebo group and 106 participants (7%) in the BCG vaccine group could not be located; total mortality was 633 participants (44%) in the placebo group and 632 participants (41%) in the BCG group. The overall rate of cancer diagnosis was not significantly different in BCG vaccine vs placebo recipients (hazard ratio, 0.82; 95% CI, 0.66-1.02), including for lymphoma and leukemia. The rate of lung cancer was significantly lower in BCG vs placebo recipients (18.2 vs 45.4 cases per 100 000 person-years; hazard ratio, 0.38; 95% CI, 0.20-0.74; P = .005), controlling for sex, region, alcohol overuse, smoking, and tuberculosis.
Conclusions and Relevance:
Childhood BCG vaccination was associated with a lower risk of lung cancer development in American Indian and Alaska Native populations. This finding has important health implications given the high mortality rate associated with lung cancer and the availability of low-cost BCG vaccines.
(Nicholas T. Usher; Suyoung Chang; Robin S. Howard; et al Adriana Martinez; Lee H. Harrison; Mathuram Santosham; Naomi E. Aronson. JAMA Netw Open. 2019;2(9):e1912014. doi:10.1001 / jamanetworkopen.2019.12014)
Original Investigation Oncology; September 25, 2019