A scientific journey through viral immunology, vaccines, and neuroinflammation

The foundations of a scientific voyage

My academic journey has humble beginnings. I grew up in a small mill town, at the gateway to the scenic ‘Yorkshire Dales’ in northern England, the daughter of immigrants who arrived after the Second World War. My father was a refugee from his homeland (Latvia) annexed by the Soviet Union, and my mother came from war-torn Europe in search of opportunity. From them, I inherited a deep curiosity for knowledge, a respect for hard work, and an enduring belief in the transformative power of education. Their lives shaped not only my aspirations but also my understanding of how migration enriches the social, economic, and intellectual fabric of the societies migrants come to call home. At a time when migration is often debated in narrow terms, their example continues to inform my commitment to scholarship, meaningful contribution, and extending opportunities to others that had previously shaped my own academic journey.

My initial career ambition was to pursue dentistry, attracted by its integration of scientific knowledge, technical precision, and patient care. However, from dissection classes of earthworms and rodents at grammar school, I soon realized that manual dexterity was not my forte and that my strengths in science lay elsewhere. Inspired by a teacher who vividly conveyed the emerging possibilities of recombinant DNA and monoclonal antibody technology and the excitement of discoveries just beginning to transform medicine, I chose instead to pursue a degree in Biomedical Sciences, majoring in Microbiology at my local university. I was fortunate to spend my undergraduate summer vacations working at the Public Health laboratories in Leeds, where I gained a welcome income and valuable skills in cell culture and virology that gave me experience above and beyond the usual 3-month final year research projects of my peers when applying for doctoral studentships.

Doctoral research in neuroimmunology and virus-driven autoimmunity

For reasons I can no longer fully recall – though perhaps instinct played its part – I joined the laboratory of Professor Sir John Newsom-Davis, a distinguished clinical neurologist, to explore the mechanisms underlying myasthenia gravis, an autoimmune disease characterized by acetyl choline receptor (AChR) autoantibodies, with a focus on infection as a triggering event – which seemed very cool to work on! My work was supervised by Dr Nick Willcox, an exceptional immunologist, and the equally eminent virologist, Dr John Oxford, then based at the National Institute for Medical Research in Hampstead, London. Both were brilliant idiosyncratic scientists. They offered intellectual freedom rather than close direction, expecting independence rather than dependence in what was a truly overambitious project for a doctoral student. In navigating that environment, I learned to think creatively, to work self-sufficiently, where needed to find collaborators for technical help, and persist through uncertainty. The intellectual and practical challenges of my doctoral training – often demanding and occasionally unforgiving – forged a resilience that has proven indispensable in facing the competitive pressures, funding constraints, and inevitable setbacks of academic life. My training experience also shaped my philosophy of doctoral education: that intellectual independence flourishes best when accompanied by strong mentorship and institutional support. As Vice Dean of Postgraduate Research, I later translated these principles into practice by reorganizing doctoral training and implemented thesis committee structures and mentorship for the first time at King’s College London to better foster the development, resilience, and long-term success of doctoral researchers.

My own doctoral research focused on the possibility that molecular mimicry between viral peptides and autoantigens could act as an environmental trigger for Myasthenia gravis.^1–3 At the time, this was a forward-looking hypothesis. Today, molecular mimicry has moved to the investigative forefront of autoimmune research, exemplified by work linking Multiple Sclerosis to Epstein-Barr virus.⁴ The conceptual framework that initially shaped my doctoral studies has thus become central to contemporary thinking about virus-driven autoimmunity.

From viral persistence to T-cell immunity: A Scripps turning point

Encouraged to broaden my scientific horizons in the United States, then a natural destination for ambitious young European investigators, I was honored to receive a highly competitive Fulbright Fellowship to join the laboratory of Dr Michael B. A. Oldstone at Scripps Research in La Jolla, California – at the time the leading center for viral pathogenesis. Although a clinician in the group had already embarked on the molecular mimicry project by the time I arrived (an initial disappointment), it proved to be a pivotal turning point. I redirected my efforts to the study of viral persistence using the murine model of infection with Lymphocytic Choriomeningitis virus (LCMV), a system that would profoundly broaden my scientific perspective. This work opened an intellectually rich and productive period of inquiry into how persistent, non-lytic viral infections can induce subtle yet consequential functional defects without overt cell destruction. I examined how LCMV infected endocrine cells could cease producing specialized hormones, while preserving housekeeping functions and remaining structurally intact. These studies demonstrated that virus-induced disease may arise not only from cytolysis but also from selective loss of differentiated “luxury” functions and metabolic rewiring toward viral replication.^5–8

Although I was then encouraged to explore potential links between viral persistence and type 2 diabetes, I found myself increasingly drawn to a different set of questions. The work of earlier postdoctoral fellows in the Oldstone laboratory – most notably Rafi Ahmed and Jacqueline Byrne – had illuminated the remarkable capacity of memory CD8⁺ T cells to control viral infection.⁹ Inspired by these insights, I persuaded Dr Oldstone to allow me to investigate how virus-specific CD8⁺ T cells recognize peptide epitopes presented by MHC class I molecules, and how this knowledge might inform vaccine design.^10–12 That immunological pivot would shape the next phase of my career.

In collaboration with J. Lindsay Whitton, then an Assistant Professor in the Oldstone laboratory, we demonstrated that a single immunodominant T-cell epitope from LCMV, expressed in a recombinant vaccine vector, could elicit cytotoxic CD8⁺ T cells (CTLs) and confer complete protection against otherwise lethal LCMV infection in certain MHC backgrounds.¹³ This study provided one of the first clear demonstrations that CTL-mediated immunity driven by a defined epitope could, on its own, provide protective immunity against a viral pathogen.¹⁴ At a time when antibody responses were widely regarded as the principal correlate of vaccine-induced protection, these findings helped broaden the conceptual framework of vaccinology. Our work established that CD8⁺ T-cell recognition of specific viral peptides presented on MHC class I molecules could be deliberately harnessed for vaccine-mediated protection.¹⁴ This represented an important conceptual shift and helped justify subsequent efforts to develop T-cell-focused vaccines, particularly for chronic or persistent infections in which the induction of durable neutralizing antibodies has proven challenging.¹⁵

Another defining insight from this period was the realization that epitope context matters profoundly. We found that delivery of a minimal 9-mer peptide epitope within a recombinant vector did not reliably prime robust CTL responses or confer protection in vivo. By contrast, embedding the identical epitope within a larger, naturally occurring protein sequence, such as a segment of a viral glycoprotein, restored both effective CTL priming and protective immunity.¹³ These studies underscored an important principle: peptide recognition in vitro does not necessarily translate into effective priming or protection in vivo. Rather, the structural and processing context of an epitope – how it is generated, processed, and presented by antigen-presenting cells – critically determines both the induction and the protective capacity of CTL responses.

This work foreshadowed my later studies with Dr Karen Anderson and Dr Joe Blattman at the ASU Biodesign Institute, where we sought to understand the determinants of CD8⁺ T-cell epitope immunogenicity.¹⁶ Analyzing nearly 10,000 MHC class I peptides, we identified a striking biochemical signature: peptides capable of eliciting strong CD8⁺ T-cell responses were enriched for hydrophobic amino acid side chains at TCR-facing positions.¹⁶ I believe that these findings helped shift the field toward a broader conceptual framework in which immunogenicity emerges from the biophysical properties of the peptide-MHC-TCR interface. MHC binding alone, while necessary, was clearly insufficient to predict immunogenicity. Instead, the immune system appeared biased toward recognizing “non-self-like” biochemical features, with hydrophobic TCR-facing residues acting as signals of foreignness and contributing to immunodominance.¹⁶ From this work, we developed the Artificial Neural Network–Hydrophobicity (ANN-Hydro) model, one of the earliest machine-learning approaches for predicting epitope immunogenicity.¹⁶ The conceptual advances arising from these studies later informed neoantigen-ranking algorithms used in cancer vaccine development, where incorporating peptide hydrophobicity improved the identification of mutations most likely to trigger productive T-cell recognition.

Back to Europe – HIV vaccine research

After completing postdoctoral training at Scripps Research, I returned to the UK to establish my independent research program at the United Medical and Dental Schools of Guy’s and St Thomas’ Hospitals (UMDS) in London. By the mid-1990s, HIV/AIDS had emerged as a major global health challenge, presenting a critical opportunity to apply my expertise in viral immunology to this rapidly evolving field. Supported by a NATO Fellowship, I undertook advanced training in the HIV laboratory of Dr Yves Riviere at the Pasteur Institute in Paris. This experience not only broadened my technical and conceptual expertise but also laid the groundwork for the next phase of my career – a research program dedicated to HIV vaccine development – a scientific challenge that continues to inspire and frustrate vaccinologists worldwide.

Influenced by Professor Thomas Lehner, then Chair of my Department at UMDS and a leading figure in mucosal immunology, I recognized early the importance of local immunity in controlling pathogen transmission. This led me to develop a research program founded on the premise that effective HIV vaccines must elicit rapid immunity at mucosal surfaces – particularly within genital and rectal tissues, the principal sites of viral entry – thereby establishing a critical first line of defense. At the time, this represented a paradigm change from prevailing strategies, which largely prioritized systemic neutralizing antibody responses.

Using a mucosal simian immunodeficiency virus (SIV) challenge model – performed in collaboration with Dr Martin Cranage’s team (Center for Applied Microbiology and Research, Porton Down, UK) – as a surrogate for HIV vaccine development, we investigated different vaccination modalities and demonstrated, using recombinant SIV protein vaccines, that effective immunization must directly target mucosal tissues or their draining lymphoid compartments to control early viral replication.^17–22 Later studies extended this work by exploring DNA vaccine technologies, particularly the use of liposomes to enhance plasmid DNA vaccine delivery to mucosal tissues.^23–27 Building on these findings, we subsequently established, for the first time, that prime-boost strategies that included vaginal or rectal vaccination recruited virus-specific cytolytic CD8⁺ T cells to cervicovaginal and rectal tissues in the SIV model, identifying these sites as critical effector compartments for protective immunity against HIV.²⁸ Together, these studies defined several principles that are now widely accepted: first, that efficient antigen delivery to lymphoid tissues shapes both the magnitude, hierarchy and anatomical distribution of protective responses^21,22; second, that protection depends on eliciting the appropriate immune effector mechanisms at the relevant site of viral entry²²; third, that effective immunity operates in a coordinated, multi-layered fashion spanning mucosal surfaces, regional lymph nodes, and systemic compartments²⁸; and finally, that optimal protection cannot be achieved through antibodies or T cells alone, but requires their coordinated action.²⁹ This framework established immune control at the portal of entry as a central principle in vaccine design and continues to inform contemporary strategies, including recombinant cytomegalovirus-based approaches developed by Louis Picker and colleagues to establish durable, tissue-resident SIV-specific CD8⁺ T-cell immunity at mucosal sites.³⁰

Building on these principles, my laboratory pivoted in 2006 toward the development of adenoviral (Ad) vaccine vectors, attracted by their capacity for high-level antigen expression and their potential to elicit the robust cellular immunity required to limit HIV escape. This strategic shift coincided with a major funding initiative from the Gates Foundation aimed at supporting high-risk, innovative vaccine approaches capable of overcoming some of the field’s most intractable scientific barriers. I was delighted to secure this highly competitive award as part of a consortium that I co-led with Dr Steve Patterson (Imperial College London), enabling us to investigate novel vaccine designs and immunization strategies to broaden HIV-specific CD8+ T-cell responses. The award also brought our group into the Collaboration for AIDS Vaccine Discovery (CAVD), providing access to an exceptional collaborative network and critical scientific resources.

Within months of the CAVD award activation, the field was upended by the abrupt termination of the landmark STEP clinical trial, a proof-of-concept study of an Ad5-vectored HIV vaccine, after interim analyses suggested increased HIV acquisition among participants with preexisting Ad5 immunity.³¹ Recognizing the urgency and provocative implications of this unexpected finding, the Gates Foundation redirected part of our program toward elucidating the underlying mechanism. Using peripheral blood samples from vaccinated participants, we demonstrated that exposure to Ad5 vectors could expand activated (CCR5+) memory CD4+ T cells expressing the mucosal homing markers α4β7 and CCR9. These cells were highly susceptible to HIV infection, providing a data-driven mechanistic explanation for how Ad5-based HIV vaccination in Ad5-seropositive individuals may have increased the pool of viral target cells at mucosal sites.³² Although several top-tier journals, including Nature and Science, were initially skeptical of the significance of these findings, Dr Robert Gallo (pioneering HIV researcher and co-discoverer of the virus) recognized their importance and supported their publication in PNAS, where he served as an editor. This highly cited manuscript³² - with >4,200 citations – helped catalyze a decisive shift away from Ad5-based HIV vaccine vectors and highlighted the critical importance of immune activation and target-cell availability as considerations in future HIV vaccine design.

Rewiring antigen presentation: dendritic cells, mucosal immunity, and vaccine design

Over the next decade, supported by funding from the Gates Foundation, UK Medical Research Council (MRC), the Biotechnology and Biological Sciences Research Council (BBSRC), and the European Union (EU), my group pursued a series of projects aimed at harnessing dendritic cell (DC) biology combined with innovative vaccine designs to generate strategically targeted, cross-reactive, tissue-localized, and functionally superior CD8+ T cell populations³³ with greater resilience to HIV diversity and immune escape. One early and unexpected finding was that viral vectors encoding ubiquitin-SIV Gag fusion proteins, designed to preferentially target the proteasome and enhance MHC class I peptide presentation by transduced human DCs, failed to improve Gag-specific CD8+ T-cell responses compared with unmodified Gag constructs.³⁴ This may have reflected the fact that the native codon-optimized Gag protein was already efficiently processed through the proteasomal pathway, while ubiquitin fusion may instead have altered antigen-presenting cell biology in a detrimental manner.³⁵ In contrast, fragmentation of the SIV Gag gene into smaller overlapping segments significantly broadened the repertoire of CD8+ T-cell responses relative to full-length Gag constructs.³⁴ These findings suggested that physical fragmentation of antigens could partially overcome epitope competition during antigen processing and presentation, thereby revealing otherwise cryptic or subdominant epitopes to CD8+ T cells. Although mechanistically and conceptually important, this strategy proved difficult to translate into a practical vaccine platform, as it required the delivery and coordinated expression of multiple antigen fragments, substantially increasing vector complexity and manufacturing burden.

A chance meeting at a scientific conference with Dr Gordon MacPherson, then at the Sir William Dunn School of Pathology, University of Oxford, revealed complementary interests in mucosal immunology: mine in understanding how DCs initiate protective immune responses to inform the rational design of mucosal vaccines and adjuvants – particularly as we had recently identified Bacillus subtilis spores as a novel microparticle vaccine adjuvant,³⁶ and Gordon’s in the immune-physiology of migratory intestinal DCs. This led to an enjoyable and productive collaboration investigating how intestinal DCs and Toll-like receptor (TLR) signaling regulate immune responses in the gut. At the time, the prevailing view was that gut DCs were largely hyporesponsive to microbial stimulation as a protective adaptation to the heavily colonized intestinal environment. Our work challenged this dogma by showing that intestinal DCs are not intrinsically inert but instead are selectively and actively regulated, enabling them to discriminate between commensal and pathogenic stimuli while maintaining immune homeostasis.^37–39 These studies helped shift the field toward a more dynamic understanding of mucosal immune regulation and had important implications for oral vaccine development by demonstrating that intestinal immune responses could be selectively engaged rather than being intrinsically suppressed. This conceptual framework anticipated later strategies using TLR ligands, particulate carriers and M-cell targeting approaches as rational mucosal adjuvants and oral vaccine delivery systems, themes that I later explored with Professor Jo Spencer, a long-standing colleague on intestinal immunity.⁴⁰

During this time, my expertise in viral immunology came to the attention of Professor Sir Robert Lechler (then Vice President, Health at King’s College London) which led to another highly successful research collaboration that challenged the prevailing binary model of antigen presentation, which at the time centered on direct presentation by virus-infected antigen presenting cells and cross-presentation of exogenous antigens. In a series of landmark studies, we demonstrated that DCs could acquire pre-formed peptide-MHC complexes from neighboring donor or virus-infected cells through membrane transfer mechanisms and present them directly to prime and activate CD8+ T cells without requiring endogenous antigen processing^41,42 - a phenomenon that became known as “cross-dressing.”⁴² This work helped redefine understanding of intercellular immune communication and is now increasingly recognized as a component of anti-viral immunity with important relevance in tumor immunity, where many cancers suppress components of the canonical cross-presentation pathway. In such settings, transfer of tumor-derived peptide-MHC complexes between cells, particularly to DCs, may contribute to anti-tumor T-cell activation, antigen dissemination, and responses to cancer immunotherapy.

A serendipitous shift toward skin immunization

Sometimes serendipity plays an unexpected role in shaping a research direction. While browsing abstracts from a conference on drug-delivery science – well outside my usual reading at the time – I came across a report describing lidocaine delivery using a fast-dissolving microneedle patch developed by TheraJect.⁴³ It immediately struck me that this technology could provide an elegant platform for needle-free vaccine delivery to skin DCs, while also addressing a major global-health challenge by reducing dependence on the cold chain in low-resource settings.

My group began developing formulations capable of thermostabilising live recombinant viral vectors and, despite having no prior pharmaceutical-engineering expertise, fabricated rapidly dissolving microneedle arrays using laser-cut molds produced through our collaboration with engineers at TheraJect. Around the same time, the Georgia Institute of Technology group led by Professor Mark Prausnitz reported the first demonstration that dissolvable microneedle vaccination could induce immune responses, an important milestone for the field.⁴⁴ My team were naturally disappointed, however, I reminded them that our focus was on the more technically demanding challenge of preserving the infectivity of live viral vectored vaccines during fabrication and storage, rather than maintaining the antigenicity of an inactivated influenza vaccine alone. Recognizing that successful clinical translation would require more than proof-of-concept delivery, I motivated my team to pivot toward understanding the immunobiology of microneedle vaccination itself. This shift in emphasis ultimately led us into a broader investigation of the immunobiology of skin vaccination, revealing how microneedle delivery could shape DC engagement⁴⁵ durable tissue-resident immunity,⁴⁶ and mucosal CD8+ T-cell responses.⁴⁷ More broadly, these studies contributed to a growing appreciation that skin immunization could imprint immune cells with homing programs directing them to distant mucosal tissues,⁴⁸ thereby influencing long-term protective immunity. Our later mechanistic study further demonstrated that interferon-γ produced by activated group 1 innate lymphoid cells (ILC1) licensed monocyte-dependent recruitment of effector CD8⁺ T cells to mucosal tissues following intradermal or microneedle-array vaccination.⁴⁹

Complement, SARS-COV-2, and neuroinflammation

During the SARS-CoV-2 pandemic, there was an urgent need to understand the mechanisms driving respiratory and systemic pathology. Drawing on my background in viral immunology, I began collaborating with Steven Sacks at King’s College London to investigate how dysregulated complement activation contributed to COVID-19 immunopathology. Our early work proposed that excessive activation of the lectin complement pathway was a major driver of the endothelial injury, thrombosis, and hyperinflammation associated with severe disease, helping to position complement inhibition as a potential therapeutic strategy.⁵⁰ We subsequently explored how lectin-pathway activation might also contribute to the Kawasaki-like multisystem inflammatory syndrome observed in children, linking complement-mediated vascular inflammation with aberrant innate immune activation.⁵¹ In later mechanistic studies, we demonstrated that the lectin-pathway recognition molecule collectin-11 could bind SARS-CoV-2 glycans and spike-expressing respiratory epithelial cells, thereby enhancing complement-mediated tissue injury.⁵² Collectively, these studies contributed to the growing recognition that complement activation is not merely a secondary consequence of infection, but an active driver of COVID-19 pathology and inflammatory tissue damage.

Another side project that became unexpectedly productive grew out of thinking about immune dysregulation in Long COVID, the cognitive symptoms many patients describe, and my early training in neuroimmunology and viral infections. In collaboration with Professor Sandrine Thuret at the Institute of Psychiatry, Psychology & Neuroscience, we identified a previously unrecognized inflammatory pathway in human hippocampal progenitor cells, where chronic TNF-α signaling triggers a type I interferon (IFNA) response that suppresses neurogenesis and promotes T-cell recruitment. Using single-cell transcriptomics and functional migration assays, we found that inflammatory signaling effectively reprograms progenitor cells away from neuronal development and toward an immune-defensive state.⁵³ Importantly, blocking IFNA receptor signaling restored neuroblast formation, highlighting a potentially tractable therapeutic pathway.⁵³ More broadly, the study provides a mechanistic link between chronic inflammation and the cognitive dysfunction seen across aging, neurodegeneration, viral infection, and mood disorders, and suggests that maladaptive neuroimmune signaling may be a convergent driver of impaired brain plasticity.

Science, service, and shared purpose

Throughout my career, it has been a privilege to help shape scientific strategy, global health policy, and research funding through leadership roles on international advisory boards, grant panels, conference initiatives, and advocacy platforms. One of the greatest honors has been recognition as a Fellow, Board member, and most recently President (2024 and 2025) of the International Society for Vaccines, where I have worked to strengthen the society’s strategic direction while championing the next generation of vaccinologists through mentorship networks, a dedicated NextGen webinar hub, and global training initiatives. I continue to be inspired by bringing together scientists, clinicians, and innovators united by the belief that vaccines can transform both human and animal health, and by applying that vision to initiatives such as the International Vaccine Institute (IVI) ACHIEVE-Africa initiative, which is advancing African-led vaccine and therapeutic sovereignty.

Looking back, however, the most rewarding part of my career has been the people. I could never individually thank all the doctoral students, postdoctoral researchers, colleagues, and collaborators who have contributed to the work over the years. Science is fundamentally a collective endeavor, and my research has depended entirely on the creativity, dedication, and generosity of the exceptional people I have had the privilege to work alongside, many of whom have profoundly shaped my own scientific journey. In many ways, that collaborative spirit and commitment to extending opportunity to others brings me back to the values instilled by my parents at the very beginning of my journey: curiosity, resilience, and a belief in the transformative power of education, migration, and shared endeavor.

Biography

Linda S. Klavinskis is Professor of Viral Immunology in the School of Immunology & Microbial Sciences at King’s College London, where she leads a research program focused on the immune mechanisms that underpin effective vaccination and protection against viral infections. Her work spans fundamental and translational immunology, with particular emphasis on understanding how innate immune responses shape adaptive immunity and how these insights can be harnessed to develop improved vaccines and immunotherapeutics.

Professor Klavinskis obtained her PhD in Immunology from University College London and subsequently undertook postdoctoral training in viral pathogenesis at Scripps Research in California. Following her postdoctoral studies, she undertook advanced research training at the Pasteur Institute in Paris, where she further developed her expertise in HIV immunology and host immune responses to infection. Throughout her career, she has made important contributions to the understanding of antigen presentation, T-cell immunity, and vaccine-induced protective responses. Her research has helped elucidate mechanisms of CD8⁺ T-cell priming, immunodominance, and antigen presentation pathways relevant to vaccine design. More recently, her laboratory has investigated innovative approaches to vaccination, including skin-targeted immunization and microneedle-based vaccine delivery platforms, with applications for HIV, influenza, and emerging viral infections. A strong advocate of translational research, Professor Klavinskis has led and collaborated on numerous national and international projects aimed at developing next-generation vaccines and adjuvants. Her work has contributed to advances in mucosal and skin immunization strategies and to a broader understanding of immune responses to viral infection and vaccination. She has authored more than 100 peer-reviewed publications and has served in a range of academic leadership roles at King’s College London, including as Vice-Dean for Postgraduate Research within the Faculty of Life Sciences & Medicine. Professor Klavinskis is an active leader within the global vaccinology community. She has served the International Society for Vaccines (ISV) in several capacities, including Board Member, General Secretary, President-Elect, President and currently President Emeritus. In these roles, she has championed international collaboration, scientific exchange, and support for early-career researchers. She is an elected Fellow of the Royal College of Pathologists and has held leadership positions in professional scientific organizations. Her career has been dedicated to advancing vaccine science and fostering the next generation of researchers working to address global infectious disease challenges.

Funding Statement

Work featured in this article was supported by funding from the Gates Foundation, European Union, UK Medical Research Council (MRC), UK Biotechnology and Biological Sciences Council (BBSRC), NIH, British Society for Antimicrobial Chemotherapy (BSAC), Wellcome Trust and fellowships from the Fulbright Commission and NATO.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary Information

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2026.2687897