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By Jamshed Arslan, Pharm D, PhD
Vaccination generates protective adaptive immune memory without the need for an actual viral infection. COVID-19 vaccines help recognize and fight off SARS-CoV-2 infection. In December 2020, US-FDA approved mRNA vaccines made by Pfizer-BioNTech and Moderna for emergency use. In January 2021, the European Medicines Agency approved a DNA vaccine made by University of Oxford with AstraZeneca for use in all age groups. All these approved vaccines (Pfizer-BioNTech, Moderna and Oxford-AstraZeneca) encourage the body to produce viral spike (S) proteins to initiate cellular and humoral immunity. To understand the correlates of immunity, it is pertinent to outline the adaptive immune control.
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When the initial innate immune response fails, the adaptive immune response steps in to eliminate the virus. Virus-specific cytotoxic CD8+ T cells kill the infected cells while B cells first release virus-specific IgM antibodies, followed by release of higher-affinity IgG or IgA antibodies under the influence of CD4+ T helper cells. If the infection is eliminated, virus-specific memory T cells and IgG/IgA-producing B cells remain, which can then be reactivated upon reinfection. Memory B cells can be detected through polyclonal stimulation, which transforms B cells into plasma cells producing specific antibodies. Memory T cells can be detected by intracytoplasmic cytokine staining with flow cytometric analysis. Studies suggest that SARS-CoV-2-specific responses from memory T and B cells can last approximately 6 months after infection.
Human peripheral blood lymphocytes (PBLs) were stained with (A) CD8 alpha Antibody (MAB1509) or (B) IgG2B isotype control antibody (MAB0041) followed by anti-Mouse IgG PE-conjugated secondary antibody (F0102B) and anti-Human CD3 epsilon APC-conjugated antibody (FAB100A).
The mRNA vaccine is packaged in fat droplets called lipid nanoparticles (LNP). This packaging system lets the mRNA slip into the human cells to produce spike proteins, making the body an inoculation factory. By contrast, the Oxford-AstraZeneca vaccine is a viral vectored vaccine that delivers double-stranded DNA (gene) rather than the relatively fragile mRNA. The replication-deficient adenoviral vector infects the cell and delivers the DNA to the cell nucleus where the cellular machinery transcribes it into mRNA; the latter is then translated into spike protein. The immune system recognizes the protruding spikes or spike fragments on the vaccinated cells and becomes activated. Killing of the vaccinated cells releases the spike protein fragments that the antigen-presenting cells take up and present on their own surface. Detection of these surface spike proteins by helper T cells raises the alarm for humoral and cytotoxic immunity.
T helper 1 (Th1) cells play a role in both cell- and antibody-mediated immunity needed for controlling intracellular pathogens like viruses. Eight weeks after the administration of a single dose of Oxford-AstraZeneca vaccine, Th1-biased response was observed in a phase 1/2 clinical trial characterized by an increased pro duction of cytokines TNF-α and IFN-γ by CD4+ T cells and detection of IgG1 and IgG3 antibodies. Cytokine-mediated “help” from Th1 also led to an abundance of CD8+ T cell phenotypes. The presence of Th1-biased response, rather than antibody-focused Th2 response, highlights the importance of cell-mediated immunity in the successful battle against COVID-19. Several reports have also suggested that SARS-CoV-2-specific T cells generating interferon-γ persist in the recovered patients even when their antibodies are undetectable. These findings also imply that serological tests for antibodies do not reflect the extent of immune memory to SARS-CoV-2.
Recombinant Human IFN‑ gamma (285-IF) reduces the Encephalomyocarditis Virus (EMCV)-induced cytopathy in the HeLa cell line in a dose-dependent manner (orange line). Inhibition of EMCV activity elicited by Recombinant Human IFN‑gamma is neutralized (green line) by increasing concentrations of IFN‑gamma Monoclonal Antibody (MAB2851).
Basic refrigeration is enough to store DNA vaccine given it has an adenoviral protein coat protects the rugged DNA cargo, while, by contrast, the delicate mRNA vaccines require subzero temperature. Viral vectors induce antibodies and cytotoxic T cells and produces a strong overall immune response in the elderly and immunocompromised individuals. However, non-viral LNP vectors for mRNA vaccines are a highly flexible platform that can avoid potential toxicity and the limited genetic capacity associated with viral vectors. These properties can partly explain the fact that mRNA vaccines (Pfizer-BioNTech, Moderna) are clinically more effective than the DNA vaccine (Oxford-AstraZeneca).
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Jamshed Arslan, Pharm D, PhD
Dr Arslan is an Assistant Professor at Salim Habib University (formerly, Barrett Hodgson University), Pakistan. His interest lies in neuropharmacology and preparing future pharmacists.
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