Ensuring vaccines are effective, accepted<\/p>\n
Immunologist\u00a0Erica Andersen-Nissen, PhD<\/a>, a principal staff scientist in the\u00a0McElrath Lab<\/a>, heads the\u00a0Cape Town Lab<\/a>\u00a0where HIV and TB vaccine trial participants\u2019 immune responses are evaluated. A deeper understanding of how our bodies are responding helps scientists improve vaccine design and assess how to determine if a candidate is more likely to be protective.<\/p>\n Andersen-Nissen and her team examine immune responses induced by new vaccines under testing, with a focus on immune cells called T cells. T cells help kill off infected cells and so are critical to the successful immune responses to pathogens like HIV and\u00a0M. tb, which get inside target cells.<\/p>\n In the trial testing BCG revaccination in teenagers, she and her team measured various T-cell populations and relevant cytokines, immune molecules that help orchestrate immune responses. They use leading-edge tests to examine what the T cells (which used highly specialized receptors to find their targets), recognize. Melding experimental assays and statistics, the inter-continental team found that certain populations of \u201chelper\u201d T cells (which support the activity of immune cells that kill infected cells and those that produce protective antibodies)\u00a0changed after BCG vaccination<\/a>.<\/p>\n \u201cThere are a lot of great South African powerhouse research labs that do amazing work here,\u201d Andersen-Nissen said. \u201cWe bring the analysis of clinical trial samples piece.\u201d<\/p>\n They have their work cut out for them:\u00a0M. tb\u00a0isn\u2019t the only mycobacterium that people are exposed to and produce immune responses to. It can be hard to distinguish immune responses to pathogenic\u00a0M. tb\u00a0from those induced by mycobacteria present everywhere in our environment. Their work points to\u00a0polyfunctional<\/a>\u00a0CD4 T cells (helper T cells that produce several cytokines) and what are known as donor-unrestricted T cells (which may be important for\u00a0effective immunity against mycobacteria<\/a>) as important players in protective TB vaccine responses.<\/p>\n The Cape Town team hands these analyses over to Fiore-Gartland\u2019s team of biostatisticians. They crunch the numbers, seeking to define important biological signatures.<\/p>\n \u201cWe seek to characterize something called\u00a0correlates of protection<\/a>,\u201d he said. \u201cEspecially in vaccines where there\u2019s partial efficacy, our goal is to understand which participants were protected, which weren\u2019t, and to compare their immune responses after vaccination to try to understand what immune responses correlated with protection.\u201d<\/p>\n VISC statisticians are currently evaluating data from two prior trials, including from the trial that test BCG revaccination in teenagers. Scientists measured whether revaccination could help prevent teenagers from sustained conversion of their\u00a0IGRA test<\/a>\u00a0(a proxy for TB infection) from negative to positive. The vaccine was\u00a045% effective<\/a>\u00a0in preventing sustained conversion.<\/p>\n These insights, which can be used to make future vaccines more effective, build on a methodological framework created for HIV vaccine trials and further honed for COVID-19 vaccine trials. But the methods aren\u2019t plug-and-play; with TB, Fiore-Gartland and his team must develop new approaches to assess vaccine-induced immune responses in people who have already reacted to\u00a0M. tb\u00a0infection or BCG vaccination. This is different than HIV vaccine trials or the first COVID-19 vaccine trials, which enroll unexposed trial participants.<\/p>\n Andersen-Nissen\u2019s team is generating immune data from the Phase 2b trial of M72, which VISC statisticians are evaluating.<\/p>\n \u201cIf we can identify protective immune responses made by M72, that could help us figure out which other vaccines to prioritize for further clinical development,\u201d Fiore-Gartland said.<\/p>\n Lamar Fleming, BS<\/a>, a staff scientist in the McElrath Lab, is gearing up to do a single-cell analysis.<\/p>\n \u201cIt\u2019s going to be one of the biggest single-cell studies ever done,\u201d Andersen-Nissen said. \u201cThe fact that we get to do it on case-control samples has the promise to yield a lot more granular detail and maybe some mechanistic potential insights about why this vaccine might work.\u201d<\/p>\n It will still be at least five years before the first TB vaccine is deployed, Shapiro said. But that\u2019s a close enough horizon that WHO is telling countries to start developing implementation plans now. Shapiro does\u00a0vaccine acceptability research<\/a>, including for potential TB vaccines.<\/p>\n \u201cWith TB, it\u2019s been hundreds of years, and we finally have a vaccine. What can we do in the next five years, before the product is ready to go, to ensure there is a strong rollout strategy?\u201d she said. \u201cFortunately, most of the work that\u2019s been done suggests that in communities hit hardest by TB, there\u2019s a lot of enthusiasm.\u201dKublin and his collaborators, including Andersen-Nissen, Fiore-Gartland and\u00a0Chetan Sheshadri, MD<\/a>, at UW, are also exploring the use of challenge studies, in which human volunteers are infected and then treated, for TB vaccine work. Also called a controlled human infection model (CHIM), this strategy can be utilized for diseases where effective treatments are available.<\/p>\n Kublin has previously used BCG as a proxy for TB in a\u00a0skin challenge model<\/a>\u00a0and is wrapping up analysis of a challenge model combining BCG and the TB drug rifampin. Now, with collaborators at Harvard University, Kublin is gearing up to develop an even more ambitious challenge model, using a strain of\u00a0M. tb\u00a0that incorporates\u00a0kill switches into the bacteria itself<\/a>. Without drugs like tetracycline or doxycycline, the bacterium \u201cundergoes suicide,\u201d Kublin said.<\/p>\n This model would better mimic natural infection, while providing several layers of safety (the kills switches, plus effective TB drugs as backups). The collaborators are doing the preclinical work needed to advance the engineered\u00a0M. tb\u00a0into a translational study, which Kublin estimates to be at least two years away.<\/p>\n \u201cThis avenue of research could really help advance both vaccine and drug studies against TB,\u201d he said.<\/p>\n New insights into TB infection and immunology<\/p>\n