Moving Towards Longer-Term Disease Protection With T Cell-Mediated Immunity

What Is a Cell-Mediated Immune Response?

Of all the disease-fighting white blood cells in the human immune system, around two-thirds are part of the innate immune system, and one-third are part of the adaptive immune system. The adaptive immune system is comprised of lymphocytes called B cells and T cells. B cells are part of the quick response team, which can detect and destroy foreign antigens through an antibody-mediated response.

Figure 1: The immune system can be divided into the innate and the adaptive immune system. Vaccinations stimulate the B cells and T cells to provide adaptive immunity to foreign antigens before they enter the body. Source

In contrast, “helper” T cells (CD4+) can be activated by an antigen-presenting cell in the body. It releases a set of signaling proteins called cytokines. These cytokines then activate “killer” T cells (CD8+) and macrophages to recognize and destroy the antigen-presenting cells. This is called the cell-mediated immune response, and can be thought of as the battlefield chain of command against pathogens.

	Humoral	Cell-Mediated
Type	Antibody-mediated response	T cell-mediated response
Site of Activity	Extracellular fluids	Location of antigen-presenting tissue
Main Cell Types Involved	B cells	T cells
Speed of Onset	Fast response upon detection	Slow response
Antigen Type	Extracellular pathogens	Intracellular pathogens, cancer cells
Method of Removal	Antibody-mediated destruction or neutralization	Cell lysis and programmed death
MHC Proteins Involved	MHC class II proteins	MHC class I proteins

Most vaccines today are designed to elicit a strong humoral response. However, more research is now being conducted into vaccines that can directly target the cell-mediated response by utilizing minimal components (epitopes) from pathogenic or oncoproteins to induce a specific immune response against infections and cancers.

The SARS-CoV2 Case

Neutralizing antibody titers and the memory B cell response is short-lived in both COVID-recovered and vaccinated patients, and the antibody response is designed to target the primary strain. There is instead evidence that the immune response is related to the magnitude and breadth of the T cell response, the type of memory T cell subsets, their cytokine polyfunctionality, and metabolic fitness.

The below immunoprofiling of T cell responses by a single dose of the AstraZeneca COVID vaccine, ChAdOx1nCov-19, performed by the Oxford-AstraZeneca team using full spectrum flow cytometry, shows the 28 days progression of lymphocytes from Phase I/II trial data.

Figure 2: A single dose of the AstraZeneca Covid vaccine provides high levels of B cells, T cells, and NK cells after 28 days. This was one of the key papers used to justify the Emergency Use Approval of the vaccine by the FDA. Source

Figure 3: A longitudinal flow cytometry study shows reduced levels of antibody titers six months after vaccination of Covid-recovery, while memory B cells and T cells activated by variants remained high. Source

A longer and wider study shows that while antibody response rapidly reduces, memory B and T cells remain high in both mRNA vaccinated and COVID-recovered after six months. Additionally, cross-binding with variant Alpha was the highest, while effectiveness is reduced for variants Beta and Delta.

Also read: Key Potential and Challenges of COVID-19 Intranasal Vaccines

This information is important as it matches the observed phenomena, where reduced antibody titers allow for breakthrough reinfections to occur, especially for new variants such as Delta and Omicron. However, stable memory B and T cells reduce the severity of the infection or reinfection, such that most cases are either mild or with no symptoms.

T Cell-Mediated Vaccination Strategies for Infectious Diseases

Long-term immunity provided by memory T cells can be achieved through, for example, peptide-based vaccines that stimulate antigen-presenting cells with different epitopes of interest. Research from mice that were immunized with a vaccine expressing SARS-CoV-2 T cell epitopes revealed decreased viral titers and lower lung pathology, even without the presence of antibodies.

A SARS-CoV-2 peptide vaccine candidate clinical trial by the University Hospital Tübingen in Germany showed that a single dose of the vaccine, termed CoVac-1, was tolerable and triggered multifunctional CD4+ and CD8+ T cell responses at a magnitude that well exceeded those brought about by natural infections or other vaccine technologies.

The peptide vaccine targets five different epitopes of the virus, which should in theory heighten its ability to reign in future escape variants.

T cell-mediated vaccination strategies are similarly explored for seasonal influenzas. Due to antigenic drift (random genetic mutations of an infectious agent resulting in minor changes), each year the flu vaccines that are provided at a public health level are offered based on best guesses of the variant that would become most infectious and pathogenic.

In such contexts, T cell-mediated vaccines such as peptide vaccines may confer some advantage and may elicit a more focused immune response toward critical neutralizing epitopes.

Therapeutic Cancer Vaccines

With the success of Moderna and BioNTech’s mRNA vaccines, there has been a renewed interest in cancer vaccines. Both companies started as cancer vaccine startups and only repurposed their technologies for infectious diseases at the start of COVID. At present, the US FDA has approved therapeutic cancer vaccines from BCG live, Sipuleucel-T, and Talimogene laherparepvec.

In general, vaccines used to fight cancer are trained to recognize and destroy cancer cells in the body. However, due to the complexities of the immune system, among the challenges include:

Suppressed and weakened immune systems
Large or advanced tumor size may need other forms of treatment to supplement the vaccine
Uncontrolled multiplication and appearance of cells
Unpredictable responses to vaccines

Also read: How PROTACs Can Help Eradicate Cancer with Our Body's Own Recycling System

Key parameters of the adaptive immune system need to be measured in the pre-clinical and clinical evaluation of T cell-mediated vaccination strategies. These parameters are best measured by high dimensional flow cytometry techniques such as full-spectrum flow cytometry.

By interrogating many different protein markers in a single sample, such as in the Oxford-AstraZeneca study, researchers can monitor the level of acute and memory lymphocyte responses in patient samples and learn about the body’s response to vaccinations.

About the author

James Hsu joined DKSH in 2019 and is part of the Business Development, Business Unit Technology team in Taiwan. In this role, he is responsible for growing the life sciences and scientific instrumentations business. His previous experience was accumulated in the bustling Asian genomics and proteomics sector, where he worked on bringing a digital PCR startup to market. James graduated from the University of California, San Diego.