On July 18, 1921, the first baby inoculated with a strain of live bovine bacteria (Mycobacterium bovis). His mother had died of an infection with the human pathogen M. tuberculosis, very similar, after his birth in a paris hospital a few hours before. The boy’s grandmother, who would care for him, also had tuberculosis (TB). In an attempt to protect the newborn from the disease, doctors administered an oral dose of what was later called the Bacille Calmette-Guérin (BCG) vaccine, to its developers Albert Calmette and Camille Guérin: the duo had grown M. bovis for more than a decade until it no longer caused disease in animals.
Today, BCG is given to more than a hundred million young children a year, basically in emerging countries, and saves tens of thousands of lives, but it provides incomplete protection and tuberculosis remains the leading infectious cause of death on the planet. Stephen Gordon, a biologist for infections in 2019, has been made even more tragic by the fact that doctors now have antibiotics to treat it. University College Dublin, tells its academics that tuberculosis is “the forgotten pandemic”.
Although BCG is lately the only tb vaccine available, researchers have been working for decades to expand a broader option and, after testing dozens of approaches, with a handful of clinical flaws, those on the floor express hope that the vaccine is close. to its beginnings in the market. ” We have a portfolio of projects, a lot of candidates,” says Thomas Hawn, an infectious disease scientist at the University of Washington. “It gives me optimism. “
While tuberculosis is sometimes thought to be a serious lung disease, causing chest pain and occasionally coughing up blood, infections in young people sometimes enlarge beyond the lungs. This can take the form of miliary tuberculosis, when the disease affects several organs and is at most fatal. without antibiotic treatment, and tuberculous meningitis, when the membranes surrounding the brain and spinal cord are infected. One of the biggest benefits of BCG is that it prevents those forms of infection. “in young people,” says Helen McShane, a vaccine researcher at Oxford University.
In adolescents and adults, who together account for more than 90% of tb cases, TB presents as the maximum non-unusual lung infection and, for some reason, BCG is less effective in preventing this form of the disease. “It provides more variable coverage against lung disease, which is now the burden of tuberculosis,” says McShane.
Interestingly, the protective force conferred by the BCG vaccine on adolescents and adults varies by geography. The vaccine has a smart efficacy in Scandinavia and other regions of higher latitudes, but coverage is weaker in populations closer to the equator. of mycobacteria discovered in equatorial regions can cause the human framework to generate an immune reminiscence that recognizes and reduces the replication of the bcg frame. “Exposure to non-tuberculous mycobacteria occurs in spaces around the world where BCG is less painted, so this is epidemiological evidence of the association,” explains mcShane.
To complicate matters, M. tuberculosis can remain dormant in the human body for decades. Another 2 billion people are latently inflamed with the virus, and when an opportunity arises, such as when the immune formula is suppressed, as is the case with HIV. -inflamed patients, the bacterium is activated, which causes the user to have poor health and most likely transmit the pathogen in the air to others.
Interestingly, the strength conferred by the BCG vaccine on adolescents and adults varies by geography.
According to experts, the key to understanding that dynamic lies in the immune response. Having coexisted with humans for millennia, Mr. Tuberculosis has developed molecular tricks to escape our immune radar and even attenuate responses when detected. the microbe enters the lungs and turns out to attract immune cells. The alveolar macrophages that patrol the lungs will engulf tuberculosis and seek to kill it, but “accidentally supply the same niche that bacteria need to enter,” Gordon says. Within macrophages, M. tuberculosis is immune to antibodies.
The “cerosa” capsule of M. tuberculosis is helping to mask the bacteria to hide them from immune recognition, Rasmus Mortensen, head of tuberculosis vaccine studies at the Statens Serum Institute in Copenhagen, wrote in an email. , once internal is to “block the maturation of the phago-lysosome, allowing it to persist and even reflect on the macrophage” . M. tuberculosis also interferes with the provision of antigens, where first-line immune mobiles provide TB antigens to auxiliary T mobiles, “delaying the onset of protective mobile T responses and restricting the effect of mobile Ts once primed. “
The framework isolates internal groups of immune cells from M. tuberculosis called granulomas, where the bacteria remain “like a ticking time bomb,” Gordon says, “waiting for the right moment when their defenses are low. “
Not all cases are serious. Most people affected by M. tuberculosis are fine; only five to five percent spread the disease. “TUBERCULOSIS and humans have been fighting and polishing their swords in opposition to each other for so long,” says Thomas Scriba, an anti-tuberculosis immunologist at the University of Cape Town in South Africa. that the balance between the winner and the loser is good.
There are two vaccine candidates in phase 3 trials, with 8 in their kits in phase 2. Further on, there are 3 phase 1 vaccines (not shown), as well as a handful of preclinical applicants attempting to move on to human trials.
VPM1002: a live BCG vaccine attenuated with a pore-forming protein of some other bacterium that allows the transfer of antigens and mycobacterial DNA from the phagosome to the cytosol (see graph below)
Revaccination with BCG: A BCG Recall
MTBVAC: a living and genetically weakened M. tuberculosis (the first vaccine of its kind to enter clinical trials) with mutations in virulence genes.
M72 ASO1: a recombinant fusion protein consisting of two M antigens. tuberculosis and an adjuvant (see chart below)
H56: IC31: a protein vaccine composed of two early secretory proteins and one latency protein, as an adjuvant
ID93 / GLA-SE: Fusion of 4 M virulence antigens. tuberculosis, combined with an adjuvant
GamTBVac: a subunit vaccine that fuses two M antigens. tuberculosis with an adjuvant
DAR-901: an inactivated preparation of the similar species Mycobacterium obuense, which causes disease (see graph)
MIP: an inactivated vaccine composed of M. indicus pranii, a fast-growing mycobacterium that causes disease.
TB / Flu04L: attenuated influenza virus administered intranasally with two M antigens. tuberculosis
Researchers don’t know exactly what BCG does immunologically to protect children, and they’re still somewhat speechless about the exact immune reaction they want for an effective vaccine in adults. Like maximum vaccines, BCG is much better at stimulating the production of antibodies, which attack microbes outdoors in mobiles, than at collecting a strong mobile T reaction. “At most all vaccines have paints by generating neutralizing antibodies, however, for TB, we don’t think neutralizing antibodies are enough,” Gordon says.
Vaccine-related protective correlates (POPs), a measurable immune reaction that is an approximation of opposite coverage to infection, will only be discovered when samples are obtained from successful placebo-controlled trials with thousands of volunteers. ‘There’s nothing. ‘” we can measure in the blood that says, ‘This patient is vaccinated and now he’s protected,'” says Nigel Curtis, a tuberculosis vaccine researcher at the Murdoch Children’s Research Institute and the University of Melbourne.
Scientists have speculated for years that a strong mobile T reaction that eliminates inflamed mobiles is very important to protect against tuberculosis. “Many studies show a desire for CD4 T mobiles (also called TH1),” says Mortensen, which appears to be “essential for infection and prevention of disseminated diseases. “He points out, however, that more CD4 T mobiles do not necessarily mean greater coverage against TUBERCULOSIS, so their abundance is not the best POPs. (Th17) T-mobiles that produce proinflammatory cytokines have been described as protective, Mortensen adds.
Tuberculosis and humans have been fighting and polishing their swords against each other for so long that the balance between the winner and the loser is very good.
To generate a vaccine that recruits and activates T mobiles well, McShane’s organization in Oxford used a modified Ankara vaccinia virus (MVA) as a vector to deliver a tuberculosis antigen, 85A. In an initial clinical trial, the resulting MVA85A vaccine “stimulated what we thought was the right type of immune reaction,” McShane recalls, in particular, the vaccine induced CD4 T mobiles that secrete interferon gamma, the phenomenon of tumor necrosis and interleukin. 2. However, in a trial conducted in South Africa in infants who in the past had been vaccinated with BCG, MVA85A did not show an improvement over vaccination with BCG alone. “To everyone’s surprise, it was discovered that the vaccine did not protect against tuberculosis,” says Curtis, who did not worry about the trial. For him, this advised that “what we measure and what we think is protective are wrong things. “The researchers concluded that the mobile T reaction point induced in the trial was not sufficient to protect after BCG.
“TUBERCULOSIS is a respiratory infection, and one of the disorders is that we almost finished reading what happens in the blood,” explains Dockrell, “but it doesn’t give an idea of what’s going on in the lungs, where there are mobile specialists “who can be very important in the fight against tuberculosis. “
BCG, or Bacille Calmette-Guérin vaccine, triggers a multi-fronted immune reaction that repels tuberculosis well in young people in emerging countries, where the disease is still common, but vaccine coverage decreases with age and the pathogen can infect adolescents and adults, causing lung disease characterized by a persistent and bloody cough. Researchers do not know which parts of the immune reaction are most critical for effective coverage and are adopting various techniques to obtain better BCG with next-generation TB vaccines. The main applicants presented here relate to the same microbe as BCG, but with some genetic modifications that researchers hope will offer greater coverage. Another requires a completely different technique with antigens manipulated from the BCG bacteria. and killed total mycobacteria of various species, adding Mycobacterium tuberculosis, which causes tuberculosis, and viral management of the genetic prescription for mycobacterial antigens.
This 100-year-old vaccine is a living but weakened form of a bovine bacterium connected to Mycobacterium tuberculosis (Mtb). Inoculation attracts first-line immune cells to the injection site. Dendritic cells and other antigen-presenting cells demonstrate portions of BCG microbe on their surface to provoke a reaction of T cells, which fight long-term infection with the pathogen and cause B cells to produce antibodies. BCG and Mtb introduce vesicles called phagosomes, where they interfere and prevent their own destruction. , while Mtb survives for a long time in the cells.
There are more than a dozen tuberculosis vaccines in clinical trials. While new TB vaccines would possibly not prevent a user from becoming inflamed, some have shown symptoms that would possibly prevent other inflamed people from progressing to the disease. “”It would be the holy grail, but it’s a top bar,” Gordon admits. “Preventing other people with latent inflammation from progressing to the disease would be a game changer. In almost all tb vaccine trials, volunteers had a latent tuberculosis infection and a previous BCG vaccine.
Two vaccines, MTBVAC in phase 2a and VPM1002 in phase 3, are being tested in adults, as well as infants and newborns, which would likely be useful for immunocompromised young people living with HIV. This is notable because vaccines that are candidates for maximum TB are tested in adolescents. and adults. ” If we could also prevent adolescents and adults from contracting TB, we wouldn’t worry about young people who want TB vaccines,” scriba says.
The candidate on everyone’s lips is M72, a protein subunit vaccine developed through GlaxoSmithKline (GSK). The vaccine includes a fusion of two M proteins. tuberculosis and an adjuvant, AS01, which GSK uses in its success against herpes zoster. Although the M72 vaccine did not look as promising in non-human primates, it reduced the incidence of pulmonary tuberculosis by 54% in 3 years in a recent trial involving more than 3,000 adults in Kenya, South Africa. and Zambia.
Because the vaccine is little more than a few proteins, “I was skeptical about its effectiveness,” says researcher Robert Wilkinson, a tuberculosis researcher at the Francis Crick Institute in London. BCG is a living vector that replicates and “seems to be the slowest turnover of herbal infection with M. tuberculosis,” Wilkinson explains, and although coverage decreases in adolescence, BCG helps keep TB out of life. childhood. ” My downp was that such a vaccine would be more productive as opposed to tuberculosis: providing an era of immune stimulation long enough to prevent herbal infections. ArrayArrayArray In this regard, I was wrong because the coverage of [M72] lasted 3 years.
Hawn, who is concerned about the progression of M72, credits the vaccine’s adjuvant, which causes an innate immune receptor called type four receptor (TLRfour) to generate a physically powerful immune reaction that uses T cells in addition to B. “Historically, we just haven’t had that power point in the adjuvants,” he says. “We have new adjuvants and our ability to cause other immune reactions in a more nuanced way has progressed a lot. “
Wilkinson notes that there were only 26 cases of tuberculosis in the placebo organization and thirteen in the vaccine organization. He says a larger trial involving tens of thousands of other people is the apparent next step before applying for emergency use authorization from a regulator.
A genetically modified edition of BCG is injected, the macrophages capture the bacterium in a phagosome, where it produces an enzyme that causes pores to form in the phagosome membrane, allowing antigens to escape to the cytosol and cause activation of the inflammasome, in the same way. like Mtb, which BCG does.
Meanwhile, the Statens Serum Institute is preparing two subunit vaccines, with its lead candidate H56 consisting of 3 antigens and a new adjuvant in phase 2b trials in Tanzania and South Africa. The institute is also introducing a subunit vaccine called H107 with 8 M-specific tuberculosis antigens. Because those antigens are shared through BCG, the H107 vaccine “does react with BCG, which means the two vaccines can be co-administered,” is Mortensen, who leads the progression of H107.
I’m very excited about mRNA vaccine technologies and I hope it won’t be long before they’re implemented for TB, as they’re obviously very agile and incredibly immunogenic.
Other protein subunit vaccines with adjuvants that looked promising in early- and intermediate-level trials failed, inhibiting Andreas Kupz, a vaccine scientist at James Cook University in Queensland, Australia, from this approach. “In general, there has been sadness around those vaccines. says he sees more hope in vaccines that adhere to BCG’s original approach.
Several new live vaccines are being developed, and one of the most complex is VPM1002, a recently genetically modified BCG in phase 3 trials that was developed as a component of an assignment led by Stefan Kaufmann at the Max Planck Institute for Infection Biology in Berlin. “We think BCG isn’t bad at all,” Kaufmann says, “but we’d like to do it for newborns, [and] preferably also for use in adults and adolescents. “Among other things for the vaccine, Kaufmann and his colleagues added the gene for a listeria pore-forming protein (listeryolisin O). Once a bacterium is wrapped through a frontline immune mobile such as a macrophage, it is sequestered in components called phagosomes. ; Phagosomal membranes perforated with Listeiolisin O to allow the leakage of molecules derived from VPM1002, which provide themselves on the moving surface to induce CD8 T mobiles to attack inflamed mobiles, and DNA leakage, which triggers proinflammatory pathways.
Two recombinant proteins of the Mycobacterium bacterium that make up the BCG vaccine are fused and injected. Fusion proteins are absorbed through immune cells, which then place them on their surface to cause an immune reaction opposite antigens. A patented adjuvant from GlaxoSmithKline (AS01) reinforces this immune reaction.
Another live vaccine candidate differs further from BCG through M itself. tuberculosis. ” There is confidence that if you can get close to simulating an herbal infection, it can be just a path to success,” wilkinson explains. Spain, which developed the so-called MTBVAC vaccine, has suppressed two virulence genes to make M. tuberculosis is safer and is now testing the modified bacteria in phase 2a trials. “A more similar reminiscence immune reaction that is likely to be protective,” says Mihai Netea, an immunologist at Radboud University in Nijmegen, the Netherlands, who participated in the MTBVAC study.
Scriba warns that since higher amounts of mycobacteria closer to the equator appear to decrease the efficacy of BCG for adults, the same phenomenon may also be repeated for new vaccines that oppose living mycobacteria. Mycobacteria interfere with the effectiveness of BCG. The question is, how much of a challenge will this be for MTBVAC and VPM1002?Scriba said. ” It will be attractive to see what happens when those vaccines are given to older people” who have been exposed If cross-reactivity between mycobacteria results in challenging protein subunit vaccines or vector-based vaccines, such as those being applied lately through the McShane Group, it is likely to prove to be the most productive option. I need to put all the eggs in one basket,” scriba says.
To reinvigose the TB vaccine landscape, researchers will need to know that BCG is not only helping to save TB, but is also preparing the immune formula to protect itself more broadly against respiratory diseases and even sepsis. after BCG was widely administered, when vaccination reduced not only tb deaths in children, but also deaths from other causes. BCG is now also used as immunotherapy for the remedy of early-level bladder cancer, put directly into the bladder to cause the patient’s disease. immune formula to attack tumors. The similar vaccine VPM1002 has also shown promise in clinical trials as a remedy for bladder cancer.
Over the past decade, researchers have gradually uncovered a mechanism for those non-specific effects, and have discovered that it is a new genetic wiring of innate immune cells, a phenomenon called trained immunity. “Essentially, other people now believe that by administering BCG, you are printing epigenetic reminiscences so that those cells respond to other upcoming infections,” says Kupz. Some scientists even believe that this general immune defense mechanism may limit to the maximum or all of the coverage provided by BCG against tuberculosis. Being tested in particular in opposition to TB, Curtis is recently leading a multinational trial of medical personnel that won BCG to see if it has an influence on SARS-CoV-2 infection.
For now, the progression of a tuberculosis vaccine is unclear through the COVID-19 pandemic. Experts who spoke to The Scientist point out that some trials of the tb vaccine have been delayed or slowed down. “It definitely pushed us back, because we would have finished this control [with M72],” Wilkinson said. In addition, tb cases have most likely gone uninformed and the remedy has been delayed in the pandemic schedule, McShane adds. “Global blockades, targeting some other pathogen, have disrupted tuberculosis control programs. »
In fact, nine of the countries with the highest levels of TB experienced a dramatic decrease, ranging from 16% to 41%, in the diagnosis and remedy of TB infections in 2020, according to the NGO Stop TB Partnership. COVID-19 had wiped out 12 years of progress in the global fight against TUBERCULOSIS. The maximum number of TB cases and deaths will likely officially decrease by 2020 due to pandemic disruptions, Kaufmann says, “but TB may kill more people than COVID-19 in 2020 because other people not diagnosed with TB will not receive treatment.
More than 95 percent of TB deaths occur in low- and middle-income countries. A study by the London School of Hygiene
A vaccine can be a component of a global strategy to combat the scourge of tuberculosis infection and mortality. “If we have a vaccine that can save you [the recipients] from getting TB disease from a latent infection or, more importantly, eliminate it. Latent infection, it would be phenomenal,” says McShane.
Even though the pandemic has temporarily hampered vaccine development, it was expected that there would be a cross-fertilization of the intense paints that have been spent on COVID-19 vaccines, even though TB is perceived as a more difficult enemy. “COVID is a less difficult goal for a vaccine. TB is much more complex,” admits McShane. However, “we want to see what classes can be learned to advance TB more quickly. Some researchers recommend that the mRNA vaccine strategy, which has strong stimulating effects on the immune system, can simply be adapted to attack tuberculosis, for example. “I’m very excited about mRNA vaccine technologies and I hope it won’t be long before they are implemented for TB as they are obviously very agile and incredibly immunogenic,” says scriba.
Whatever the answer, the researchers in the box are determined to locate it, with clinical systems moving forward. “It’s the leading cause of death among all infectious diseases,” Kupz says. “We want a better vaccine against tuberculosis.
In the 1920s, BCG was administered orally. Doctors temporarily switched to injection just under the skin, which remained standard practice for nearly a century. However, researchers are now reconsidering childbirth, considering access to the lungs and intravenous injections.
“We’re working on getting vaccines to the lungs, because that’s how TB gets into the body,” says Helen McShane of Oxford University. “And there’s animal knowledge to show that this is the way to protect. “their studies involve more potent immune responses in the lungs and blood when a tuberculosis vaccine is given in aerosol form.
“When BCG is administered directly into the lungs, either intranasally or by spraying, resident reminiscence cells are activated,” says Andreas Kupz, a vaccine scientist at James Cook University in Queensland, Australia. These are localized reminiscence T cells and, optionally, reminiscent B cells. they are ready to respond to the reappearance of an express pathogen.
These mobiles also appear to be stimulated through an intravenous infusion of BCG. A recent study in Nature reported increased cd4 and cd8 t mobile reactions in rhesus macaques that were immunized intravenously with BCG, to monkeys that obtained intranasal and intradermal administration. “through IV BCG can teach us more about the type of immune reaction needed, and then we can design other vaccines that induce that reaction,” mcShane explains.