SARS-CoV-2 Vaccines and Immune Response (L9)

SARS-CoV-2 Vaccines and Immunity

• Three vaccines that were developed in response to the COVID-19 pandemic are:
  • BNT162b2 (Pfizer/BioNTech)
  • mRNA-1273 (Moderna)
  • Ad26.COV2.S (Johnson & Johnson)

Measuring Immune Response After Vaccination

• The presence of neutralizing antibodies in the serum is the primary indicator of protection against SARS-CoV-2 infection following vaccination.
• ELISA screening is the most efficient way to detect antibodies after vaccination.
• The presence of virus-specific CD4+ and CD8+ T cells is more challenging to study.
• Flow cytometry is used to detect the presence of virally specific CD4+ and CD8+ T cells.

Antibody Responses to SARS-CoV-2 Induced by Vaccination

• Both Moderna and Pfizer vaccines create strong antibody responses.
• Antibody levels peak one week after the second dose and decline slightly after six months.
• Moderna recipients have slightly higher antibody titers than Pfizer recipients.
• Individuals with prior COVID infection and individuals who were vaccinated had a good antibody response to both Pfizer and Moderna vaccines.
• The Adenovirus (Ad26.COV2.S) vaccine induces lower initial antibody responses compared to mRNA vaccines but remains relatively stable for eight months.

Spike-Specific T Cell Responses Induced by Vaccination

• Vaccination with the Pfizer vaccine induces strong CD4+ T cell responses with a slight decline after six months.
• CD8+ T cell levels are elevated but not as high as CD4+ after the second dose of the vaccine.
• T cell levels are significantly elevated compared to individuals who are not vaccinated.
• Gamma interferon (IFN-γ), a major cytokine produced by Th1 cells, is produced in high amounts by CD4+ and CD8+ T cells following vaccination.
• Despite a slight decrease, IFN-γ levels remain elevated after six months of receiving the second vaccination.

SARS-CoV-2 Variants of Concern

• Numerous SARS-CoV-2 variants of concern (VOC) have emerged with varying degrees of transmissibility and resistance to existing immunity.
• Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P.1) VOCs emerged between late 2020 and May 2021.
• Mu (B.1.621) and Delta (B.1.617.2) emerged between May and November 2021.
• Omicron (B.1.1.529) emerged in November 2021 and is highly transmissible even in populations with high levels of immunity.

SARS-CoV-2 Vaccination and Variants

• CD4+ and CD8+ T cells are unaffected by mutant variants of the virus because the protective T cell response is not solely specific to the Spike-receptor binding domain.
• Vaccination leads to the development of Spike-specific CD4+ memory T cells detected in nearly 100% of individuals weeks and six months after the second dose.
• Similar responses are observed for mRNA and adenoviral vector vaccines.
• CD8+ memory T cells are detected in 70-90% of individuals after the second dose and 45-65% at six months.
• Both mRNA and adenoviral vector vaccines elicit similar responses.
• Both CD4+ and CD8+ memory T cells recognize diverse Spike epitopes and viral variants, including Omicron.

T Cell Responses to Viral Variants

• T cells from individuals vaccinated with mRNA or adenovirus vaccines show recognition of SARS-CoV-2 variants, including Omicron.
• Most T cell epitopes are conserved across different variants.
• Memory T cell responses are maintained for 6-7 months after vaccination.
• The repertoire of T cell epitopes reveals 11 Spike epitopes recognized by CD4+ T cells and 10 Spike epitopes recognized by CD8+ T cells.

Hybrid Immunity

• A decrease in neutralizing antibodies can be attributed to the emergence of viral variants.
• Breakthrough infections occur due to the emergence of viral variants.
• Hybrid immunity refers to the immune response observed in individuals who have experienced a natural infection prior to vaccination or in vaccinated individuals who have had a breakthrough infection.
• Extensive studies examine T and B cell immunity in vaccinated individuals with breakthrough infections and responses to viral variants.

Hybrid Immunity: CD4+, CD8+, and B Memory Cells

• Individuals with hybrid immunity have increased CD4+ and CD8+ memory T cell responses compared to natural infection or vaccination alone.
• These individuals have circulating CD4+ and CD8+ memory T cells, and tissue-resident memory cells are generated.
• B memory cells specific to the Receptor Binding Domain (RBD) have more somatic hypermutation and affinity maturation compared to vaccination alone.

Antibody Response in Hybrid Immunity

• Neutralizing antibody titers improve in individuals with hybrid immunity.
• The breadth of neutralization of SARS-CoV-2 variants increases.
• Antibody titers are 5 to 17 times higher after six months compared to vaccination alone.

Hybrid Immunity: Breakthrough Infection and Vaccination

• Antibodies from individuals with breakthrough infections and vaccination after natural infection broadly neutralize SARS-CoV-2.
• SARS-CoV-2 infection before or after vaccination significantly boosts the neutralizing antibody response compared to two doses of vaccine.
• Vaccination after recovery from natural SARS-CoV-2 infection ("hybrid immunity") substantially increases the potency and breadth of the humoral response to SARS-CoV-2.
• This hybrid immunity elicits significantly higher amounts of cross-variant neutralizing antibodies compared to vaccination of naive individuals alone.
• Strong immunity from hybrid immunity might be due to higher clonal turnover of B cells and greater somatic hypermutation in SARS-CoV-2 recovered individuals compared to naturally infected or naive vaccinated individuals.

Memory B Cells

• Memory B cells persist after infection, evolve continuously, and mature by acquiring somatic mutations in their variable-region genes to improve affinity through an ongoing germinal center response.
• Understanding how mRNA vaccination influences the Memory B cell pool shaped by prior exposure to SARS-CoV-2 and its capacity to neutralize variants is crucial.
• It is important to investigate differences and evolution of Memory B cells from naive vaccinees compared to SARS-CoV-2-recovered individuals.
• Vaccination boosts the expansion of high-affinity Receptor Binding Domain-specific memory B cells in COVID-19-recovered individuals, eliciting a strong serum antibody response that includes cross-neutralizing antibodies to variants of concern.
• Vaccination of SARS-CoV-2-naive individuals induces low neutralizing antibodies to variants, and the maturation of RBD-specific memory B cells is less pronounced.

Strong Immunity in Hybrid Immunity

• Strong immunity against SARS-CoV-2 in vaccinated individuals with prior natural infection is due to:
  • Receptor Binding Domain-specific memory B cells
  • Neutralizing antibodies to viral variants

Advantages of Hybrid Immunity Over Vaccination

• Individuals with hybrid immunity have a broader repertoire of virus-specific antibodies.
• They exhibit robust T cell responses, including T cells specific to not only the Spike protein but also other SARS-CoV-2 proteins.
• CD4+ T cells in individuals with hybrid immunity are characterized by a functional profile of interferon gamma (IFN-γ) and low IL-10 production.

SARS-CoV-2 Antibody Detection in Patients

• The detection of SARS-CoV-2-specific IgM and IgG in patients is the basis for disease diagnosis, utilized in conjunction with RT-PCR-based tests.
• Reports indicate that patients with severe disease often have an increased IgG response and higher titers of total antibodies, which are associated with worse outcomes.
• High levels of antibody detection may indicate that the FC portion is binding to antibodies that have receptors specific to the FC region, leading to enhanced viral replication.
• If an antibody binds to a virus, a cell may become engulfed, facilitating viral replication.
• This phenomenon refers to immune backfire or antibody-dependent enhancement (ADE).

Antibody-Dependent Enhancement

• Antibody-dependent enhancement (ADE) is a process where a virus leverages antibodies to aid infection.
• Non-neutralizing antibodies can bind to macrophages, facilitating the virus's entry into those cells and potentially accelerating viral replication.

Conclusion

• Both natural infection, vaccination, and breakthrough infections elicit adaptive T and B cell responses to SARS-CoV-2.

This quiz explores the various SARS-CoV-2 vaccines developed during the COVID-19 pandemic, including their mechanisms and effectiveness. It also covers how to measure the immune response post-vaccination and the antibody responses induced by these vaccines.