Determination of the effectiveness of COVID-19 vaccination using T cell receptor repertoire


Researchers have been working at an unprecedented rate to develop vaccines against coronavirus disease 2019 (COVID-19) to limit the ongoing pandemic caused by the rapid spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). To date, several COVID-19 vaccines have received emergency use authorization (EUA) from global regulators, and vaccination programs have begun in most countries of the world.

Examination: The T cell receptor repertoire reflects the dynamics of the immune response to vaccination. Image credit: NIAID

How do vaccines protect individuals from disease?

Vaccines offer prophylactic immunization against specific diseases by triggering a sustained, adaptive immune response that generates immunological memory and protects against future infections. Typical, T cells offers adaptive immune protection and the humoral antibody response is mediated by B cells. After vaccination, the B cells are activated and produced neutralizing antibodies which can bind to target proteins of a virus and subsequently protect the individual from the disease. The cell-mediated immune response is associated with the activation of effector CD4 T cells, which stimulate B cells to produce antibodies. These cells can also use other cells, such as macrophages, which have microbicidal functions. Activated CD8 T cells eliminate virus-infected cells. Both CD4 and CD8 memory T cells persist long after vaccination and are ready to become effector T cells. Previous studies have shown that natural killer cells also possess memory-like behaviors.

Through vaccines, pathogenic protein subunits are introduced into an individual that stimulate the response of the B and T cells. Some of the common types of vaccines are inactivated viruses, vectors that infect cells to generate viral proteins, messenger RNA (mRNA) and viral proteins. mRNA COVID-19 vaccines are likely to induce both CD4 and CD8 T cell responses.

Determining the effectiveness of the vaccine

In the current scenario, it is extremely important to measure the effectiveness of the vaccines as well as vaccination strategies. Typically, the response to vaccines is evaluated by detecting and measuring antibodies to viral proteins present in the serum. Vaccine response can also be evaluated by detecting activated B and / or T cells.

One of the shortcomings of antibody-based assays (eg ELISA) is that they cannot detect low levels of antibodies, which may be sufficient to protect against a particular disease. In many cases, the level of antibodies drops significantly long after vaccination or natural infection, but they provide strong protection against the disease. Detectable levels of antibodies can be developed, for antibody-based assays, at least a few weeks after vaccination.

ELISpot is a technique used to detect T and B cells that respond to the vaccine. This assay can measure interferon-gamma or granzym B from the activated cells. Although this method can indirectly assess the activity of immune cells, it is not always accurate.

Evaluation of vaccine efficacy via T cell receptor (TCR) repertoire

A new study published on bioRxiv* The preprint server has assumed that the T cell receptor repertoire (TCR) can measure the response to vaccines, as it will identify the TCR of clones that respond to the vaccination.

Previous studies have revealed that TCR is a heterodimer of two trans-membrane polypeptide chains (TCRα and TCRβ) linked by covalent disulfide bonds, and a complete TCR repertoire may reflect the T cells present in an individual.

Researchers have developed a new and accurate method known as Tseek, which is impartial and provides sensitive profiling of TCRα and TCRβ chains or TCR repertoire by sequencing the TCR a and b chains. To evaluate the efficacy of Tseek in the evaluation of vaccine responses, researchers compared the responses to mRNA COVID-19 vaccines and the annual influenza vaccines. Based on epidemiological and antibody data, the vaccines have very different rates of efficiency, i.e. the effectiveness of the COVID-19 vaccine is 90%, whereas the influenza vaccine is 30%.

Clustering of T cell repertoire (CDR3 a) from the Covid / Influenza vaccine samples.  Distances between samples were defined for CDR3 data using the Jensen-Shannon metric (an information theory goal, supplementary material).  The heat maps show the distance between pairs of samples, while the dendrograms show the samples grouped by individual.  A) Covid CDR3 b. The first dose is s1, the second dose is s2, d0 is the sample before vaccination, d7 is 7 days after vaccination, w3 is 3 weeks after vaccination.  For each individual, the two samples after the second vaccine dose (s2_d7 and s2_w3) are collected separately from the two samples after the first vaccine dose (s1_d7 and s1_w3), suggesting that different sets of T cells respond to the two doses.  The second dose expands the virus epitopes targeted, which is likely to enhance the immunity provided by the vaccination.  (Fig. 3A shows the corresponding tree) B) Flu b CDR3 19_20 refers to the influenza season 2019-2020, d0 is the sample before vaccination, d7 is 7 days after vaccination, m1 is 1 month after vaccination.  Clustering after vaccine dose does not occur in some individuals (B, D), and the m4 and m6 samples appear to have lost
Clustering of T cell repertoire (CDR3 a) from the Covid / Influenza vaccine samples. Distances between samples were defined for CDR3 data using the Jensen-Shannon metric (an information theory goal, supplementary material). The heat maps show the distance between pairs of samples, while the dendrograms show the cluster of samples of an individual. A) Covid CDR3 b. The first dose is s1, the second dose is s2, d0 is the sample before vaccination, d7 is 7 days after vaccination, w3 is 3 weeks after vaccination. For each individual, the two samples after the second vaccine dose (s2_d7 and s2_w3) are collected separately from the two samples after the first vaccine dose (s1_d7 and s1_w3), suggesting that different sets of T cells respond to the two doses. The second dose expands the virus epitopes targeted, which is likely to enhance the immunity provided by the vaccination. (Fig. 3A shows the corresponding tree) B) Flu b CDR3 19_20 refers to the influenza season 2019-2020, d0 is the sample before vaccination, d7 is 7 days after vaccination, m1 is 1 month after vaccination. Clustering after vaccine dose does not occur in some individuals (B, D), and the m4 and m6 samples appear to have lost the “memory” of dose, and the T cell response lasts no longer than 2-3 months. Although there are responsive clones for each influenza season (Tables 2A, B), the relative lack of clustering of the tree after vaccine dose, in contrast to the covid vaccine data, suggests that the response is “weaker” and has more individual and seasonal variation. FIG. S3 shows data for b.

Researchers have evaluated the different results of the vaccines using the Tseek method. In this context, they used PBMC samples from individuals who consistently received annual influenza vaccines over several influenza seasons for several years. In addition, researchers collected PBMC samples from individuals who received two doses of COVID-19 mRNA vaccines. Neutralizing antibody titers were also measured in COVID-19 vaccine samples.

This study revealed that an individual’s TCR signature develops gradually over the years in response to infections. Researchers found that SARS-CoV-2 vaccination induced a broad-spectrum T cell response involving many expanded clones; however, this was not the case for the influenza vaccine, which elicited a narrower response involving fewer clones. In addition, many T cell clones provided temporal details that are typically not obtained from antibody measurements, especially before the antibodies are detectable.

Conclusion

The current study revealed that the TCR repertoire is a valuable biomarker for the study of immune responses to the vaccine. The authors highlighted some of the benefits of using Tseek to determine the response to vaccines, including that it is a non-invasive approach, rapid assessment of vaccine efficacy, ie. within a few days after vaccination, and a very sensitive and specific method. The current study really shows that TCR repertoire sequencing can be effectively used for early and sensitive measurement of the adaptive immune response to vaccination, which can help improve the selection of the immunogen and optimize the vaccine strategy.

*Important message

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered essential, guide clinical practice / health-related behavior or be treated as established information.

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