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  • Next generation Covid-19 vaccines: Broader T cell responses in focus

Next Generation COVID-19 Vaccines – The Importance of Proper T Cell Induction to Address the Variants in a Lasting Manner

The COVID-19 vaccines approved or in development so far focus predominantly on the viral Spike protein, and are assessed based on their ability to stimulate antibody production. Antibodies are considered to be gold standard in vaccine development, but experience gained during the pandemic suggests that vaccines that stimulate broader immune responses including T cell responses are needed for long-term control of SARS-CoV-2 (1).

This piece examines the drawbacks of current vaccines, discusses why T cell-inducing vaccines are key to long-term immunity and why T cell responses to COVID-19 are broad and robust against variants and finally why Immunitrack is well positioned to take part in T cell inducing-vaccine development projects.

Current COVID-19 Vaccines Have Drawbacks

COVID-19 vaccine development so far has mainly focused on stimulating the production of antibodies against a viral protein known as Spike. Spike is present on the surface of SARS-CoV-2, and besides being critical for the virus’ ability to enter cells, it also gives coronavirus its crown-like appearance when viewed under a microscope.

Given its location and function, vaccine developers rationalised that a vaccine that blocks Spike, through the development of anti-Spike antibodies, would be an effective strategy to prevent infection by SARS-CoV-2. Unlike T cells that only spring into action once infection has set in, antibodies, if present in high enough numbers, can block infection entirely by binding to the virus and preventing it from entering cells.

However, despite current efficacy rates above 90 % for most of the approved COVID-19 vaccines, antibodies wane over time, and experts are already discussing the need for boosters and annual revaccination to keep yearly infection rates under control.

As well as uncertainties about how long immunity will last after the current vaccines, concerns exist about their ability to control coronavirus variants in the long term. The Novavax, Johnson & Johnson and Astrazeneca COVID vaccines were all less effective in preventing mild COVID-19 in South Africa where the 501Y.V2 variant is the dominating strain, in comparison to other countries where the same variant is less widespread.

T Cell-Inducing Vaccines Are Key to Long-Term Immunity

Concerns about antibody-driven COVID vaccines have prompted scientists to look at other parts of the immune system that might provide longer lasting and broader immune responses, and T cells are in the spotlight.

It’s well known as proper CD8 and CD4 T cell activation are critical for clearance of viruses such as influenza and human immunodeficiency virus (HIV), and multiple studies indicate that this is also the case for SARS-CoV-2. Furthermore, while T cells can’t prevent infection, they are crucial for clearing established infections and they may be the difference between a mild and a severe infection (2).

In one study conducted last year, 70 % of recovered COVID-19 patients were found to have SARS-CoV-2-specific CD8 T cell responses and all patients in the same study had CD4 T cell responses (3). The importance of the T cells is further highlighted by studies revealing that antibody responses to SARS-CoV-2 are short-lived and may even cause or aggravate virus-associated lung pathology (4, 5).

With respect to coronavirus variants, T cells have the advantage of being able to target viral epitopes derived from any SARS-CoV-2 protein, unlike neutralising antibodies that can only bind surface proteins from circulating virus particles. As a result, it is likely more difficult for variants to escape T cell immunity than neutralising antibody responses.

T Cell Responses to COVID-19 Are Broad and Robust Against Variants

Recent research led by Alessandro Sette at the La Jolla Institute for Immunology in California found that people infected with SARS-CoV-2 generally produce T cells that can target at least 15-20 SARS-CoV-2 epitopes from several viral proteins (6). Such a broad immune response would be more difficult for a coronavirus variant to escape than an antibody-based response based on Spike epitopes alone.

Preliminary findings from the UK further support the potential of T cell-inducing vaccines to control novel variants. Here, researchers found that the UK and South African variants displayed some resistance to antibodies from previously infected individuals and to a lesser extent from vaccinated individuals. However, the impact of these variants on T cell responses from previously infected individuals was much less pronounced, in other words the T cell responses could protect against future infections with variants (7).

Study results published late last year also suggest that while antibody responses following SARS-CoV-2 infection might not be long-lasting, immune memory might be achieved through virus-specific memory T cells (8).

Immunitrack Is Ready For Next-Generation COVID-19 Vaccines

The ability to screen the entire SARS-CoV-2 proteome for T cell-inducing epitopes is crucial to developing a vaccine that can stimulate broad T cell immune responses. Immunitrack’s high-throughput epitope screening technology has the capacity to do this against a diverse range of human leukocyte antigens (HLAs) from all major human populations.

Immunitrack’s expert competences in predicting and analysing T cell responses positions it as a key partner for T-cell inducing vaccine development and it is already working with an industrial partner to develop a population-specific COVID-19 vaccine. Tailor-making a vaccine to a specific population is a unique approach to vaccine development, and Immunitrack can do this because it has access to a broad HLA library and unmatched expertise in working with many diverse HLA genes.

Given the importance of T cell responses in clearing viral infections, T cell-inducing vaccines have potential in controlling diseases beyond COVID-19, and Immunitrack is already involved in a number of projects in this area, e.g., a T cell- and antibody-inducing vaccine for Zika virus in collaboration with the University of Liverpool, UK.

What Immunitrack can offer:

High throughput:

  • High-throughput HLA peptide production
  • High-throughput stability assessment of HLA/epitopes
  • Broad portfolio of HLAs to cover all ethnicities: Caucasian, Asian, Hispanic and African

Unmatched accuracy:

  • Immunitrack’s proprietary stability assay platform NeoScreen can more accurately rank epitopes according to immunogenicity than any other in vitro or in silico platform
  • NeoScreen has a superior hit rate when identifying T cell responses compared to affinity-based assays
Immunitrack’s comprehensive HLA restriction study of SARS-CoV-2 Spike-derived epitopes ▸
Identification of Novel CD4 and CD8-Stimulating Epitopes From COVID-19 ▸

References

  1. M. Hellerstein, What are the roles of antibodies versus a durable, high quality T-cell response in protective immunity against SARS-CoV-2? Vaccine X 6, 100076 (2020).
  2. A. Nelde et al., SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition. Nature Immunology 22, 74-85 (2021).
  3. A. Grifoni et al., Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 181, 1489-1501.e1415 (2020).
  4. L. Liu et al., Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight 4,  (2019).
  5. F. Tang et al., Lack of peripheral memory B cell responses in recovered patients with severe acute respiratory syndrome: a six-year follow-up study. J Immunol 186, 7264-7268 (2011).
  6. A. Tarke et al., Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases. Cell Rep Med 2, 100204 (2021).
  7. D. T. e. a. Skelly, Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern. Research Square,  (2021).
  8. P. F. Cañete, C. G. Vinuesa, COVID-19 Makes B Cells Forget, but T Cells Remember. Cell 183, 13-15 (2020).

Get in Touch

If you would like to learn more about how Immunitrack could assist in your T-cell inducing vaccine development project, please don’t hesitate to reach out to us.

Please contact us by email at info@immunitrack.com, by phone using the numbers listed below, or use our online contact form ▸

Tel. +45 28682159

COVID-19 Links

  • Spike CD4+ and CD8+ T Cell Epitope Study ▸
  • Spike Mutations – Potential Implications for Vaccine T Cell Responses ▸
  • Identification of Novel CD4 and CD8-Stimulating Epitopes From COVID-19 ▸
  • Study of COVID-19 vaccine candidate epitopes reveals low performance of common tools ▸
  • Spike CD4+ and CD8+ T Cell Epitope Kits ▸
  • COVID-19 CD8+ Tetramer Panel for Immune Monitoring ▸
  • COVID-19 Efforts: Overview ▸
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Immunitrack’s mission is to provide the research community with tools to select or redesign drug candidates at the early stage of R&D but also to provide reagents to monitor lead drug candidates effect on patient’s immune system.

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info@immunitrack.com
Tel. +45 28682159

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