For decades, vaccination has been strongly associated with the prevention and priming of the immune system to protect against future infections. Although this principle still holds, the concept has expanded in recent years. Vaccines are now being developed not only to prevent disease but also as therapeutic tools designed to retrain the immune system to target tumors, control chronic infections such as human immunodeficiency virus, and influence complex disease processes.

Unlike classic prophylactic vaccines, which are designed to generate long-lasting immune memory against external pathogens, therapeutic vaccines are intended to modulate the existing immune response in a precise and targeted manner. The goal is to correct dysfunction or strengthen immune control when it is lacking.

These approaches are often tailored to an individual’s biological profile, reflecting advances in immunology and technological platforms, such as multi-epitope mRNA vaccines, neoantigen-based vaccines, and formulations combined with immunotherapy.

Together, these developments are shaping a new category of therapeutic vaccines that blur the traditional boundary between prevention and treatment. In this evolving field, Spanish oncology and translational immunology research is becoming increasingly involved in clinical trials and vaccine development.

Oncology remains the primary field for the development and validation of therapeutic vaccines. Conventional chemotherapy and radiotherapy act in a nonspecific manner, damaging both tumors and healthy tissues. In contrast, therapeutic vaccines introduce a different strategy based on the targeted activation of the immune system against tumor antigens. Some of the earliest clinical approaches, such as talimogene laherparepvec, a genetically modified oncolytic herpes simplex virus, in melanoma, and sipuleucel-T in prostate cancer, explored this strategy using modified viruses or the patient’s own cells loaded with tumor antigens.

Currently, research is focused on teaching the immune system to accurately recognize tumor cells and attack them selectively and sustainably over time. These strategies aim to reduce the tumor burden, delay disease progression, prevent relapses, and improve survival, particularly in individuals with minimal residual disease after surgery. Such strategies include individualized neoantigen vaccines, multiepitope mRNA constructs, synthetic peptides, and dendritic cells engineered to stimulate CD4-positive and CD8-positive T-cell responses.

Melanoma has emerged as the principal translational model because of its high mutational burden and sensitivity to immune checkpoint blockade and has become the primary model for translating these advances into clinical benefits.

A 2025 study published in Cell evaluating the NeoVax and NeoVaxMI platforms demonstrated broad, polyclonal, mutation-specific T cell — responses against tumor mutations. The results showed significant improvements by optimizing antigen selection, dosing, and formulation.

A 2025 review of next-generation mRNA vaccines for melanoma suggests that this tumor represents a favorable model for refining these technologies and progressing toward broader and more standardized clinical use. According to this review, vaccine performance depends primarily on antigen selection and optimization of multiple features of the RNA construct itself, including codon tuning, secondary structure, and chemical modifications intended to enhance stability while limiting nonspecific immune activation. Structural elements, such as the 5′ and 3′ untranslated regions, Cap1 type cap, and poly(A) tail length, are also critical, as they directly influence mRNA half-life and protein expression levels.

These molecular advances have been accompanied by parallel progress in the field of drug delivery. Lipid nanoparticles remain the dominant platform, although formulations have been refined to improve tissue and cellular targeting. In addition, hybrid delivery approaches that combine lipid nanoparticles with tumor cell membranes or extracellular vesicles are under investigation, enabling some antigens to be displayed on the particle surface, while others are encoded intracellularly. Collectively, these developments support the potential for more effective and adaptable vaccines with improved scalability and clinical applicability.

Therapeutic Vaccines in HIV

Therapeutic vaccines targeting chronic infections remain experimental. Although immune activation has been consistently demonstrated, clinical efficacy data remain limited, and no therapeutic vaccines have been widely approved for these indications. Most of the available evidence is derived from phase 1 or 2 trials and immunomodulation studies of recurrent respiratory infections or persistent viral infections, such as HIV, hepatitis B virus, hepatitis C virus, herpesviruses, and Epstein-Barr virus.

In HIV infection, therapeutic vaccination aims to modify host-virus interactions after infection have been established. In recent years, early phase clinical trials have evaluated next-generation therapeutic vaccine candidates, including HB 500, which is being assessed in phase 1b studies in individuals with suppressed viral loads receiving antiretroviral treatment. These studies have focused on safety, immunogenicity, and the capacity to induce targeted immune responses, as well as their potential contribution to strategies seeking a functional cure.

The aim is to reduce or discontinue antiretroviral therapy while keeping the virus under control through enhanced CD8 + T-cell responses and more durable antibody activity against viral reservoirs that evade conventional treatment. Although these findings remain preliminary, therapeutic vaccination could emerge as a complementary approach to existing treatments.

In recurrent respiratory infections, the use of sublingual and mucosal bacterial vaccines as immunomodulators has been associated with reduction in the frequency, duration, and severity of infectious episodes in prospective studies. Although these interventions are primarily preventive, their capacity to reduce complications and antibiotic use suggests their potential therapeutic role, particularly in the context of antimicrobial resistance.

Other Chronic Infections

Additional therapeutic vaccine candidates under investigation in Europe target chronic infectious diseases. According to a report from Vaccines Europe, two candidates have reached more advanced stages of development: an mRNA vaccine targeting Cutibacterium acnes, currently in phase 2 trials for acne, and an mRNA vaccine against herpes simplex virus, also in phase 2, and positioned within the field of sexually transmitted infections.

Both vaccines employ mRNA technology, incorporating modified nucleosides and lipid nanoparticle delivery systems, which is consistent with the prevailing trends in the European vaccine sector. This report identified approximately 48 RNA-based vaccine candidates, the majority of which originated in Europe. Phase 2 status indicates that initial safety and immunogenicity data in humans are available, although these products remain far from being commercially available.

Although this review does not focus on antitumor vaccines, it includes vaccines targeting oncogenic infectious agents, such as hepatitis B virus, human papillomavirus, and Epstein-Barr virus, which may combine preventive and therapeutic potential against the underlying risk.

Overall, evidence suggests that therapeutic vaccines hold a limited but clearly defined role in the European portfolio. Broader adoption will depend on more clearly defined regulatory frameworks and value assessment criteria that support innovation while facilitating the translation of effective and accessible treatments.

This story was translated from El Medico Interactivo, part of the Medscape Professional Network.