At the Amsterdam Institute for Immunology and Infectious Diseases (AI&I), we focus on three key research areas: Post-Acute Infection Syndromes (PAIS), Immunomonitoring, and Vaccination. Regularly, we highlight one of these areas, exploring essential knowledge, challenges, and real-world impact. In Q3 2026, our spotlight is on Vaccination. In this article, written in collaboration with AI&I researcher Prof. Joke den Haan, we explore the challenges and developments in vaccination research. 

Vaccination is a cornerstone of modern medicine, designed to train the immune system to recognize and fight disease. Research in this area is crucial, as it helps us develop new strategies to prevent and treat both infectious diseases and cancer.

Different diseases, different goals

Vaccine development for infectious diseases started already with the smallpox vaccines in the 18th century. These vaccines are usually given preventively to healthy individuals with robust immune systems and aim to induce neutralizing antibodies that prevent pathogens from infecting the body. The science behind antibody responses has been investigated for more than 100 years and researchers have focused on measuring antibodies in the blood and optimizing vaccines to generate strong antibody responses. Neutralizing antibodies are especially important for viral infections and bacterial toxins, as they can prevent infection and toxic effects. Well-known are the childhood vaccines that include vaccines against poliovirus and diphtheria toxins, but also more recently introduced vaccines against e.g. Human Papilloma virus induce antibody titers that prevent viral infection and thereby prevent the development of cervical cancer. 

Cancer vaccines, on the other hand, are generally provided therapeutically to patients who already have cancer and often have weakened immune systems. These vaccines must stimulate cytotoxic (CD8+) T cells that can directly kill tumor cells and this is harder to achieve. For a long time, vaccine research focused mainly on infectious diseases and antibodies, and only recently has attention shifted to cancer and optimizing T cell responses.

The evolution of immunology

‘Our understanding of the immune system has changed enormously over the years,’ says Prof. Joke den Haan. ‘For centuries, we focused on antibodies and B cells, but it wasn’t until the 1960s that scientists discovered T cells, which are produced in the thymus and play a crucial role in immunity.’ Joke explains that it took decades to unravel what T cells actually recognize. ‘It was only in the 1980s and 1990s that we learned T cells respond to small peptide fragments of proteins, presented by HLA molecules on the surface of cells. That discovery opened up a whole new field in immunology.’

Cytotoxic T cells are now known to be essential for cancer immunology because they can kill abnormal cells, including cancer cells. ‘One of the biggest challenges,’ Prof. den Haan notes, ‘is that cancer cells are very similar to normal cells. Therefore it is harder to elicit immune responses against cancer cells compared to pathogens’.

She adds, ‘Thanks to advances in sequencing technology over the past 20 years, we can now quickly identify mutations in cancer cells and see how they differ from healthy cells. Every patient’s cancer is unique, and with modern algorithms, we can predict which mutations are most likely to be recognized by T cells. This is a huge step forward for personalized medicine.’

Personalized cancer vaccines

Today, researchers can sequence a patient’s tumor, identify mutations, and predict which ones are promising targets for vaccines. These vaccines can be made in two forms: synthetic long peptides (SLPs) or mRNA vaccines, similar to those used for COVID-19. mRNA vaccines are taken up by cells, which then express the peptides, while SLPs can be directly taken up by antigen-presenting cells (APCs).

To trigger an immune response, adjuvants, substances that activate the immune system, are often added to SLP vaccines. The immune system is usually in a resting state and must be actively stimulated to respond. mRNA vaccines already activate the immune system on their own and work without adding extra adjuvant. However, both types of vaccines still tend to stimulate rather low levels of cytotoxic T cells and require many injections with the vaccines. 

‘Making cancer vaccines more effective starts with stronger cytotoxic T cell responses: that’s what we’re working on in my lab.’

Joke den Haan

Professor of Translational Immunology with a Focus on Cancer Vaccines at the Department of Molecular Cell Biology and Immunology 

Our contribution: enhancing Cytotoxic T Cell responses

‘Our research is all about finding ways to boost cytotoxic T cell responses,’ Prof. den Haan explains. ‘One of the key challenges is making sure vaccines are taken up by the right antigen-presenting cells, because that’s crucial for activating strong T cell responses.’

Prof. den Haan continues: ‘We are experimenting with adding an extra molecule to the vaccine, so it is more efficiently captured by the right immune cells. Recently, our team developed a nanobody that binds directly to antigen-presenting cells. By attaching a tumor antigen to this nanobody, we can ensure the antigen is presented much more effectively, which leads to a stronger T cell response.’

She adds, ‘This innovation really holds promise for making cancer vaccines more effective.’

Challenges in Vaccination Research

Researchers in the vaccination field face several major challenges:

Predicting Immunogenicity: Immunogenicity refers to the ability of a substance, such as a mutation or an antigen, to provoke an immune response in the body. It remains difficult to accurately predict the immunogenicity of identified mutations. Even when mutations are found in patients or tumors, it is not always clear which ones will be recognized by T cells. Each person has a unique T cell repertoire and is tolerant to their own peptides, so a mutation may not necessarily trigger a strong immune response. Current methods cannot reliably forecast which mutations will be most effective as vaccine targets.

Inducing Cytotoxic T Cell Responses: Most vaccines, including synthetic long peptide and mRNA vaccines, tend to induce more helper (CD4) T cell responses than cytotoxic (CD8) T cell responses. Achieving robust cytotoxic T cell activation is still a challenge. This may be due to vaccines being taken up by the wrong type of antigen-presenting cell (APC), as some APCs are better at activating helper cells, while others are more effective at stimulating cytotoxic T cells. Researchers are working on strategies to direct vaccines to the right APCs and to optimize adjuvants, the signals that alert the immune system, to improve cytotoxic T cell responses.

Immunodominance and Cancer Resistance: Cancer has a remarkable ability to escape immune responses. While cancer vaccines aim to generate immune responses in lymph nodes or the spleen, T cells must then migrate to the tumor and kill cancer cells. Cancer can suppress these steps, leading to T cell exhaustion and reduced effectiveness. Combining cancer vaccines with other therapies is essential to overcome these barriers. For example, oncolytic viruses can selectively kill tumor cells and create local inflammation, while therapies targeting stromal cells or using antibody-drug conjugates can help expose and attack the tumor.

Combination Therapies: The best approach may be combination therapies, as they make it harder for cancer to escape immune attack. By integrating multiple strategies, such as vaccines, oncolytic viruses, and antibody-drug conjugates, researchers hope to achieve more effective and durable responses.

Ethical and social issues in vaccination research

Vaccination research, especially in the context of cancer and advanced therapies, raises several important ethical and social considerations. 

High costs and accessibility: The cost of personalized mRNA vaccines can be extremely high, often €100,000 to €200,000 per patient. These vaccines are still mainly in phase 1 and 2 clinical trials and are not yet widely available. ‘It is a huge challenge,’ says Prof. den Haan, ‘because these advanced treatments are promising, but only a limited number of patients can actually access them. We need to think about how to make these innovations more affordable and widely available.’

Combination therapies: Combining vaccines with checkpoint inhibitors is a promising approach. Checkpoint inhibitors help prevent immune exhaustion and work well in patients who already have an immune response. When combined with vaccines, even patients who initially lack an immune response can benefit. However, these therapies are expensive and not accessible to everyone.

Timing and patient selection: Early clinical trials often included patients with a high tumor load and late-stage disease, which suppressed immune responses and limited vaccine effectiveness. Now, vaccines are being tested in earlier stages, after the primary tumor has been removed, to prevent relapse or recurrence. Joke notes, ‘We are learning that timing is crucial. Using vaccines earlier in the disease process seems to be much more effective, but it also raises questions about who should receive these therapies and when.’

Off-the-Shelf vaccines: There is ongoing research into vaccines targeting antigens shared by multiple patients, allowing for “off-the-shelf” vaccines that can be used more broadly. Some mutations, known as oncogenic drivers, are common across different patients and can be targeted by these vaccines. Clinical trials are showing promising results, but the challenge remains to match the right antigens to the right tumors and patient groups.

HLA Allele limitations: Some vaccines are limited to patients with certain HLA alleles, restricting their applicability and raising concerns about fairness and inclusivity.

Overall, while advances in vaccination research offer hope for more effective treatments, they also highlight the need for equitable access, careful patient selection, and ongoing attention to ethical and social implications. ‘We must keep asking ourselves how to balance innovation with fairness and accessibility,’ Prof. den Haan emphasizes.

Conclusion 

Vaccination research continues to evolve, with significant progress being made in both infectious disease and cancer vaccines. While antibody responses have been optimized for decades, the focus is now shifting to harnessing the power of T cells, especially for cancer. Personalized vaccines, new technologies, and a deeper understanding of the immune system are paving the way for more effective treatments. Although challenges remain, the field is rapidly advancing, offering hope for better prevention and therapy in the future.

Discover more articles in this series:

• VACCINATION TOPIC 101 | With Marit van Gils

Text: Joke den Haan and Esmée Vesseur