Vaccination-Induced Immunity to SARS-Cov-2 Lecture

Vaccination- Induced Immunity to SARS-COV-2 Christine Rohowsky- Kochan, PhD Professor – NJMS September 24, 2024  3 vaccines that were made in response to the COVID-19 pandemic: 1. BNT162b2 – Pfizer/BioNTech 2. mRNA-1273 – Moderna 3. Ad26.COV2.S – Johnson & Johnson – Janse...

Vaccination- Induced Immunity to SARS-COV-2 Christine Rohowsky- Kochan, PhD Professor – NJMS September 24, 2024  3 vaccines that were made in response to the COVID-19 pandemic: 1. BNT162b2 – Pfizer/BioNTech 2. mRNA-1273 – Moderna 3. Ad26.COV2.S – Johnson & Johnson – Janseen Important to understand the mechanistic immune correlates of vaccine protection, to optimize the delivery and efficacy of the vaccines. Measuring adaptive immune responses after vaccination Main correlation of protection against SARS-CoV-2 infectionis the presence of neutralizing antibodies in the serum after vaccination. ELISA screening would be performed to assess presence of antibodies. This is the most efficient way of detecting antibodies following vaccination. Presence of virus-specific CD4+ and CD8+ T cells is more difficult to study. Flow cytometry would be used to test for the presence of virally specific CD4+ and CD8+ T cells.  Antibody responses following vaccination with Moderna and Pfizer mRNA vaccines Measuring antibody titers in both Moderna and Pfizer vaccine recipients All vaccine recipients: produced good antibody response for both vaccines. Individuals previously uninflected, and vaccinated: Moderna had insignificantly higher antibody titer. Individuals that had previous COVID infection, and vaccinated: Good antibody response after being vaccinated by either Pfizer or Moderna. Antibody responses to SARS-CoV2 induced by vaccination Anti-Spike-Receptor Binding Domain levels 6 months after 2nd vaccine dose are similar to levels after 1st vaccine dose or levels in individuals with natural infection. Highest antibody levels were seen one week following the 2nd dose of COVID vaccine. Antibody levels decreased slightly after 6 months from 2nd dose.  Antibody responses Both mRNA vaccines induced strong antibody responses that decline by 6 months and further decrease by 8 months Antibody titers were greater in individuals receiving mRNA- 1273 Moderna vaccine compared to titers in individuals receiving the BNT162b2 Pfizer vaccine The Adenovirus (Ad26.COV2.S) vaccine induced lower initial antibody responses however they remained relatively stable for 8 months Serum concentration of neutralizing antibodies needed to provide durable protection from infection and transmission remains unclear Spike-specific T cell responses induced by vaccination with BNT162b2 Pfizer vaccine Looking at adaptive T cell response induced by the Pfizer vaccine CD4+ T cells: very strong responses. Slight decline after 6 months of 2nd vaccine. CD8+ T cells: elevated levels of CD8+ but not as elevated as CD4+ after administration of 2nd vaccine. T cells significantly elevated when compared to no vaccination. IFN-γ CD4+ and CD8+ T Cells after vaccination Looked at gamma interferon (the major cytokine produced by Th1 cells) levels in individuals that were vaccinated with the COVID vaccine. Results indicate that there are very high amounts of gamma interferons produced by CD4+ and CD8+ after 1st and 2nd vaccination. Despite slight decrease in gamma interferon, it was still being produced after 6 months of receiving 2nd vaccination. CD4+ defined as the Th1 phenotype. Memory T cells after vaccination CD4+ cells CD8+ cells Naïve T cells Increased CD4+ and CD8+ indicating positive response to vaccine after 2nd administration. 2 types of important memory cells: effector cells and central memory cells. Central memory T cells: increased CD4+ T cells. CD8+ T cell activity detected. Effector Memory T cells: increased CD4+ T cells. CD4+ T cells will increase protective functions.  T cell mediated immunity T cell immunity is generated after 1st vaccine dose and increases following 2nd dose Robust CD8+ T cell response is seen within two weeks following vaccination with BNT162b Pfizer vaccine similar to what occurs after natural infection. Virus-specific CD4+ T cell responses are induced; Th1 profile and T follicular phenotype but not Th2; detected by within a week following vaccination, peak after boost and decline after 4 months T follicular phenotype is critical in providing help to B cells to make antibodies. Magnitude of T cell responses similar to that seen with natural infection T cell responses correlate with neutralizing antibody response Vaccine-induced cellular responses are markedly enhanced in individuals with a history of prior natural infection  Vaccination Memory B cells Memory B cells are generated after 2nd dose of vaccine Affinity maturation of B memory cells is lower after vaccination than after natural infection Affinity maturation refers to the continuing antibody response post infection. Frequency of B cells increases 3-6 months after vaccination Dependent on T follicular helper cells and germinal centers Significant decrease of memory B cell recognition of the spike variants especially Omicron were observed.  SARS-COV2 Variants of Concern Numerous SARS-CoV-2 variants of concern (VOC) with differing levels of transmissibility and resistance to existing immunity have sequentially emerged, and spread widely since the beginning of the COVID-19 pandemic Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P.1) VOCs - late 2020 to May 2021 period Mu (B.1.621), Delta (B.1.617.2) – May –Novmeber 2021 Omicron (B.1.1.529) - November 2021 - ability to spread in populations with high levels of immunity  Vaccination Both CD4+ and CD8+ T cells were unaffected by the mutant variants of the virus because the protective T cell response is not only specific to Spike- receptor binding domain. This allowed T cells to see mutant variants. CD4+ memory T cells Spike-specific responses detected in almost 100% of individuals weeks and at 6 months after 2 nd vaccine dose Similar response for mRNA and adenoviral vector vaccines CD4+ memory T cells were of the Th1,Tfh and CD4- cytotoxic phenotype. Recognize diverse Spike epitopes and viral variants including Omicron CD8+ memory T cells Detected in high 70-90 % of individuals after 2nd vaccine dose and in 45-65% of individuals at 6 months after 2nd dose Similar response to mRNA and adenoviral vector vaccines Recognize diverse Spike epitopes and viral variants including Omicron T cell responses to viral variants after SARS-CoV-2 vaccination T cells from individuals vaccinated with either the mRNA vaccines or the adenovirus vaccine recognize the SARS-Cov-2 variants including Omicron Most T cell epitopes are conserved in the different variants Memory T cell responses preserved for 6-7 months after vaccination T cell epitope repertoire revealed 11 spike epitopes recognized by CD4+ T cells and 10 spike epitopes recognized by CD8+ T cells  Hybrid Immunity Decrease in neutralizing antibodies may be due to the emergence of the different viral variants Break thorough infections due to emergence of viral variants Hybrid immunity – immune response in individuals who have either had a natural infection prior to vaccination or in vaccinated individuals who have had a break thorough infection Many studies looking at T and B cell immunity in vaccinated individuals with breakthrough infections and encompassing response to viral variants  Hybrid Immunity CD4+ and CD8+ memory T cells Increased CD4+ and CD8+ memory T cell responses in hybrid immunity compared to natural infection or vaccination alone. Individuals with hybrid immunity had CD4+ and CD8+ memory T cells circulating and tissue resident memory cells are generated. B memory cells B memory cells specific to RBD-binding memory cells have more somatic hypermutation and affinity maturation than after vaccination Antibody Improvement in neutralizing antibody titers Increase breadth of neutralization of SARS-CoV-2 variants Titers were between 5-17-fold higher at 6 months than after vaccination alone  Antibody levels in vaccinated individuals with natural infection or breakthrough infections Antibodies from individuals with breakthrough infections and vaccination after natural infection broadly neutralize SARS-CoV-2 Breakthrough infection is an infection that occurs after vaccination. SARS-CoV-2 infection before or after vaccination gives a significant boost to the neutralizing antibody response compared with two doses of vaccine. Vaccination after recovery from natural SARS-CoV-2 infection “hybrid immunity” – substantially increases potency and breadth of humoral response to SARS-CoV-2 Elicits substantially higher amounts of cross-variant neutralizing antibodies compared to those induced by vaccination of naïve individuals alone Strong immunity from hybrid immunity may be due to high clonal turnover of B cells and greater somatic hypermutation in SARS-CoV-2 recovered compared with naturally infected or naïve vaccinated individuals.  Memory B cells Memory B cells – persist after infection, evolve continuously and mature by acquisition of somatic mutations in their variable-region genes to improve affinity through an ongoing germinal center response. Understanding how mRNA vaccination affects the Memory B Cell pool shaped by previous exposure to SARS-CoV-2 and determine its capacity to neutralize variants is critical Important to decipher how Memory B Cell from naïve vaccinees differ and evolve in comparison with SARS-CoV-2 recovered individuals Vaccination boosts expansion of high affinity Receptor Binding Domain-specific memory B cells in COVID-19-recovered individuals and elicit a strong serum antibody response that includes cross-neutralizing antibodies to variants of concern Vaccination of SARS-CoV-2 naïve individuals induce low neutralizing antibodies to variants and maturation of RBD-specific memory B cells is less pronounced Strong immunity against SARS-CoV-2 in vaccinated individuals with prior natural infection (Hybrid immunity) is due to: Receptor Binding Domain- specific memory B cells Neutralizing antibodies to viral v  Advantages of hybrid immunity over vaccination Individuals with hybrid immunity have broader repertoire of virus- specific antibodies S-specific memory B cells Robust T cell response T cells specific not only for S but also to other SARS-CoV-2 proteins CD4+ T cells characterized by a functional profile of interferon gamma and low IL-10 production.  Detection of SARS-CoV-2- specific IgM and IgG in patients is the basis for disease diagnosis, in conjunction with RT- PCR- based tests Reports that patients with severe disease frequently had an increased IgG response and a higher titer of total antibodies, which was associated with worse outcome. Antibody- dependent enhancement (ADE) of SARS- CoV-2 infection High levels of antibody detection may be indicative that the FC portion is binding to antibodies that have receptors specific to the FC region causing enhanced viral replication. If antibody is binding to virus, cell may become engulfed, aiding viral replication.  Immune backfire – enhancement of viral replication. Antibody-dependent enhancement (ADE), a process in Immune which a virus leverages antibodies to aid infection. Non-neutralizing antibodies may bind to macrophages and Enhancement help the virus enter those cells and accelerate viral replication.  Adaptive T and B cell responses to SARS- CoV-2 are elicited after natural infection, vaccination, and in breakthrough infections. They are essential for viral clearance, provide robust memory, and mediate recognition of viral variants and may underpin protection against severe infection and death.