When most people think about vaccines, they imagine a shot, a sore arm, and perhaps a layer of protection against disease. But inside the body, vaccination triggers something far more intricate: a vast conversation between cells, molecules, and memories. Some cells recognise an invading pathogen. Others amplify the alarm. Some remember the encounter for years. And somewhere in the middle of all this lies a question that has fascinated Dr Vamsee Mallajosyula for much of his life: how do immune cells coordinate with such precision, and can we learn to measure that coordination well enough to design better vaccines?
This year, Vamsee joined the National Centre for Biological Sciences as an Assistant Professor, bringing with him a lab that sits at the intersection of immunology, protein engineering, quantitative biology, and vaccine science.
For Vamsee, the immune system has always been intriguing because it operates across scales. The same biological problem can be studied at the level of proteins, cells, tissues, or entire organisms. An infection inside a human body can also be dissected molecule by molecule in a laboratory.
“It’s one of the most complex biological systems,” he says. “And you can ask questions about it at many different levels.”
That fascination first shaped his doctoral work at the Indian Institute of Science, where he trained in molecular biophysics. At the time, one of the major challenges in immunology was the search for a universal influenza vaccine.
Influenza viruses evolve rapidly. The proteins on their surface mutate frequently enough that vaccines have to be reformulated almost every year to keep up with circulating strains. But certain regions of the virus remain relatively stable across variants. The hope behind a universal flu vaccine is simple: instead of training the immune system to recognise only the changing parts of the virus, can scientists redirect immunity toward these conserved regions and come up with a longer-lasting protection?
Vamsee’s work approached this challenge through protein design. His research involved engineering and characterising vaccine candidates and studying how immune systems responded to them in animal models. In multiple collaborations with researchers at Merck & Co., Hong Kong University, and NIH, he worked on understanding whether vaccines could be designed to provoke immune responses against conserved regions of influenza viruses, especially regions that are normally less visible to the immune system.
“But over time, another question began to occupy my mind. Designing a vaccine was one challenge. Understanding how humans respond to vaccines was another,” says Vamsee.
That curiosity eventually took him to the laboratory of immunologist Mark Davis at Stanford University, where he shifted from protein engineering toward human immunology. There, he studied immune responses to seasonal influenza vaccines and became interested in one of immunology’s enduring problems: understanding why individuals respond differently to vaccination and how to detect the exceedingly rare immune cells responsible for pathogen recognition.
The immune system contains millions of distinct B cells and T cells, each capable of recognising different molecular targets. Identifying the few cells responding to a vaccine can be extraordinarily difficult. It is something like identifying a handful of specific voices in a packed stadium.
During his postdoctoral work, Vamsee developed a technology called “spheromers,” to enhance the detection of antigen-specific immune cells.. The approach allows researchers to isolate rare pathogen reactive T and B cells, providing powerful new tools for studying immunity and advancing the development of TCR-based therapies and therapeutic antibodies.
Modern biology has become exceptionally good at generating data. We can now sequence genomes in hours, predict protein structures using artificial intelligence tools, and measure thousands of molecular features from a single sample. For Vamsee, the next challenge is figuring out how to synthesize this large, complex data into meaningful insights about how biological systems coordinate and function
At NCBS, his lab will focus on understanding how T cells ( a central class of immune cells) help organise and shape immune responses.
Vaccines work not simply because the body encounters a pathogen, but because immune cells communicate effectively enough to build long-term protection. Among the key coordinators in this process are helper T cells, which influence how other immune cells respond, including the production of antibodies by B cells.
“What is the level of T cell help required to drive an effective immune response?” Vamsee asks. “If we can measure that accurately, we might eventually learn how to tune immune responses more precisely.”
That question has implications beyond infectious disease. T cells are involved in autoimmune disorders, where the immune system mistakenly attacks healthy tissue, and in cancer immunotherapy, where engineered T cells are increasingly used to target tumours. Understanding how these cells behave ( both quantitatively, and qualitatively) could help researchers design more effective vaccines and therapies.
A major challenge, however, is that immune responses are notoriously variable. The same vaccine can produce different outcomes across individuals depending on genetics, environment, infection history and age. Measuring T cell responses consistently remains difficult, partly because immune cells themselves are highly dynamic and heterogeneous.
Vamsee’s lab plans to approach this problem through what he calls “high-dimensional immune profiling.” bringing together cutting-edge experimental and computational approaches to study immune responses at unprecedented depth. By integrating spheromers, human immune organoids, protein engineering, large-scale cellular measurements, and advanced machine learning methods, the lab aims to uncover the principles that govern coordinated immune responses.The lab will initially work with human clinical samples, including COVID-19 vaccine samples available through NCBS repositories, to establish experimental and analytical pipelines.
India presents a particularly interesting context for this kind of work. Human immune responses are shaped not only by biology, but also by geography, nutrition, pathogen exposure, and genetic diversity. Studying immunity in diverse populations may reveal patterns that are often missed in datasets dominated by Western cohorts.
While machine learning and computational analyses have become common in modern biology, Vamsee feels that mathematical and theoretical modelling remain comparatively underexplored in immunology. He sees NCBS with its strong communities in biophysics, theory, and quantitative biology as an ideal environment to build these connections.
Conversations with theorists, he says, often force experimental biologists to rethink what they measure and why. Sometimes, the absence of the “right” data becomes visible only when someone attempts to build a model from it.
That collaborative spirit shapes how he thinks about science more broadly. Having benefited from interdisciplinary collaborations throughout his career, Vamsee hopes to build a lab culture where students are encouraged to pursue their own ideas and where curiosity matters as much as technical expertise.
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